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  • 1.
    Elovsson, Greta
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brown, Mikaela
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    A Novel <i>Drosophila</i> Model of Alzheimer's Disease to Study Aß Proteotoxicity in the Digestive Tract2024In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 25, no 4, article id 2105Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta (A beta) proteotoxicity is associated with Alzheimer's disease (AD) and is caused by protein aggregation, resulting in neuronal damage in the brain. In the search for novel treatments, Drosophila melanogaster has been extensively used to screen for anti-A beta proteotoxic agents in studies where toxic A beta peptides are expressed in the fly brain. Since drug molecules often are administered orally there is a risk that they fail to reach the brain, due to their inability to cross the brain barrier. To circumvent this problem, we have designed a novel Drosophila model that expresses the A beta peptides in the digestive tract. In addition, a built-in apoptotic sensor provides a fluorescent signal from the green fluorescent protein as a response to caspase activity. We found that expressing different variants of A beta 1-42 resulted in proteotoxic phenotypes such as reduced longevity, aggregate deposition, and the presence of apoptotic cells. Taken together, this gut-based A beta-expressing fly model can be used to study the mechanisms behind A beta proteotoxicity and to identify different substances that can modify A beta proteotoxicity.

  • 2.
    Björk, Linnea
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Amino-Acid Side-Chain Nanoarchitectonics for Tuning the Chiroptical Properties and Supramolecular Structure of Pentameric Oligothiophenes2024In: ChemPhotoChem, E-ISSN 2367-0932Article in journal (Refereed)
    Abstract [en]

    Oligothiophenes with specific photophysical properties and molecular organization are of great interest, since this class of materials are used in organic electronics and bioelectronics, as well as biosensing. Herein, 8 different pentameric oligothiophenes, denoted proteophenes, with different amino acid substitution patterns at distinct positions along the thiophene backbone were investigated. Spectroscopic and microscopic studies of the ligands revealed the formation of optically active self-assembled materials under acidic or basic conditions. The distinct photophysical characteristics, including induced circular dichroism, as well as the supramolecular structures of the assemblies deduced from light scattering and transmission electron microscopy, were highly influenced by the positioning of distinct amino acid moieties along the thiophene backbone. Proteophenes functionalized with only glutamate residues or these functionalities in combination with hydrophobic valine moieties formed fibrillar structures with excellent chiroptical properties under acidic conditions. In addition, the amino acid functionality at the beta-position of distinct thiophene moieties influenced the induced circular dichroism pattern observed from the proteophenes. Overall, the obtained results demonstrate how changes in the position of various amino acid functionalities, as well as the chemical nature of the amino acid side chain functionality greatly affect the optical properties as well as the architecture of the self-assembled materials. Self-assembled Proteophenes. Oligothiophenes with distinct amino acid side-chain functionalities along the conjugated backbone displayed distinct chiroptical and structural properties in acidic or alkaline solutions. The distinct photophysical characteristics, as well as the supramolecular structures of the assemblies were highly influenced by the chemical nature of the amino acid, as well as the positioning of distinct amino acid moieties along the thiophene backbone.image

  • 3.
    Parvin, Farjana
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Haglund, Samuel
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    Wegenast-Braun, Bettina
    Univ Tubingen, Germany; Univ Tubingen, Germany.
    Jucker, Mathias
    Univ Tubingen, Germany; Univ Tubingen, Germany.
    Saito, Takashi
    RIKEN, Japan; Nagoya City Univ, Japan.
    Saido, Takaomi C.
    RIKEN, Japan.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Per
    Karolinska Inst, Sweden.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and AppNL-F Mice2024In: ACS Chemical Neuroscience, E-ISSN 1948-7193, Vol. 15, no 10, p. 2058-2069Article in journal (Refereed)
    Abstract [en]

    Amyloid plaques composed of fibrils of misfolded A beta peptides are pathological hallmarks of Alzheimer's disease (AD). A beta fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of A beta fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how A beta fibril structures in situ differ in A beta plaque of different mouse models expressing familial mutations in the A beta PP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and A beta-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and App(NL-F) have different fibril structures within A beta-amyloid plaques depending on the A beta PP-processing genotype. Co-staining with A beta-specific antibodies showed that individual plaques from APP23 mice expressing A beta PP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact A beta 40 fibrils, and the corona region is dominated by diffusely packed A beta 40 fibrils. Conversely, the A beta PP knock-in mouse App(NL-F), expressing the A beta PP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact A beta 42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice &gt;12 months, appears strongly promoted by A beta 40 and was hence minuscule in App(NL-F). These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.

  • 4.
    Calvo-Rodriguez, Maria
    et al.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA; AbbVie Inc, MA USA.
    Kharitonova, Elizabeth K.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Snyder, Austin C.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Hou, Steven S.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Sanchez-Mico, Maria Virtudes
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Das, Sudeshna
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Fan, Zhanyun
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Serrano-Pozo, Alberto
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Bacskai, Brian J.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid ß aggregates in vivo in a mouse model of Alzheimer's disease2024In: Molecular Neurodegeneration, E-ISSN 1750-1326, Vol. 19, no 1, article id 6Article in journal (Refereed)
    Abstract [en]

    BackgroundReactive oxidative stress is a critical player in the amyloid beta (A beta) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in A beta plaque-associated dystrophic neurites in the AD brain. Although A beta causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether A beta plaques and soluble A beta oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.MethodsWe expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and A beta plaques.ResultsFor the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both A beta plaque deposition and direct application of soluble oligomeric A beta onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting A beta plaque burden.ConclusionsConsidering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.

  • 5.
    Nunez-Diaz, Cristina
    et al.
    Lund Univ, Sweden.
    Andersson, Emelie
    Lund Univ, Sweden.
    Schultz, Nina
    Lund Univ, Sweden.
    Poceviciute, Dovile
    Lund Univ, Sweden.
    Hansson, Oskar
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Wennstrom, Malin
    Lund Univ, Sweden.
    The fluorescent ligand bTVBT2 reveals increased p-tau uptake by retinal microglia in Alzheimer's disease patients and <i>App</i><SUP>NL-F/NL-F</SUP> mice2024In: Alzheimer's Research & Therapy, E-ISSN 1758-9193, Vol. 16, no 1, article id 4Article in journal (Refereed)
    Abstract [en]

    Background Amyloid beta (A beta) deposits and hyperphosphorylated tau (p-tau) accumulation have been identified in the retina of Alzheimer's disease (AD) patients and transgenic AD mice. Previous studies have shown that retinal microglia engulf A beta, but this property decreases in AD patients. Whether retinal microglia also take up p-tau and if this event is affected in AD is yet not described. In the current study, we use the p-tau-specific thiophene-based ligand bTVBT2 to investigate the relationship between disease progression and p-tau uptake by microglia in the retina of AD patients and AppNL-F/NL-F knock-in mice, an AD mouse model known to demonstrate extracellular A beta plaques and dystrophic neurites in the brain from 6 months of age.Methods Evaluation of bTVBT2 specificity and its presence within microglia was assessed by immunofluorescent staining of hippocampal sections and flat-mount retina samples from non-demented controls, AD patients, 3-, 9-, and 12-month-old AppNL-F/NL-F knock-in mice and 12- and 18-month-old wild type (WT) mice. We used ImageJ to analyze the amount of bTVBT2 inside Iba1-positive microglia. Co-localization between the ligand and p-tau variant Ser396/Ser404 (PHF-1), A beta, phosphorylated TAR DNA binding protein 43 (pTDP-43), and islet amyloid polypeptide (IAPP) in the brain and retina was analyzed using confocal imaging.Results Confocal imaging analysis showed that bTVBT2 binds to PHF-1- and AT8-positive aggregates inside retinal microglia, and not to A beta, pTDP-43, or IAPP. The density of bTVBT2-positive microglia was higher in cases with a high A beta load compared to those with a low A beta load. This density correlated with the neurofibrillary tangle load in the brain, but not with retinal levels of high molecular weight (aggregated) A beta 40 or A beta 42. Analysis of AppNL-F/NL-F knock-in mouse retina further showed that 50% of microglia in 3-month-old AppNL-F/NL-F knock-in mice contained bTVBT2. The percentage significantly increased in 9- and 12-month-old mice.Conclusion Our study suggests that the microglial capability to uptake p-tau in the retina persists and intensifies with AD progression. These results also highlight bTVBT2 as a ligand of interest in future monitoring of retinal AD pathology.

  • 6.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lantz, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Ge, Junyue
    Univ Gothenburg, Sweden.
    Hanrieder, Jorg
    Univ Gothenburg, Sweden; UCL, England.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thiophene-Based Ligands for Specific Assignment of Distinct Aß Pathologies in Alzheimer's Disease2024In: ACS Chemical Neuroscience, E-ISSN 1948-7193Article in journal (Refereed)
    Abstract [en]

    Aggregated species of amyloid-beta (A beta) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different A beta deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of A beta deposits found in AD brain tissue. A dual-staining protocol based on two ligands, HS-276 and LL-1, with different photophysical and binding properties, was developed and applied on brain tissue sections from patients affected by sporadic AD or familial AD associated with the PSEN1 A431E mutation. When binding to A beta deposits, the ligands could easily be distinguished for their different fluorescence, and distinct staining patterns were revealed for these two types of AD. In sporadic AD, HS-276 consistently labeled all immunopositive A beta plaques, whereas LL-1 mainly stained cored and neuritic A beta deposits. In the PSEN1 A431E cases, each ligand was binding to specific types of A beta plaques. The ligand-labeled A beta deposits were localized in distinct cortical layers, and a laminar staining pattern could be seen. Biochemical characterization of the A beta aggregates in the individual layers also showed that the variation of ligand binding properties was associated with certain A beta peptide signatures. For the PSEN1 A431E cases, it was concluded that LL-1 was binding to cotton wool plaques, whereas HS-276 mainly stained diffuse A beta deposits. Overall, our findings showed that a combination of ligands was essential to identify distinct aggregated A beta species associated with different forms of AD.

  • 7.
    Sulheim, Einar
    et al.
    Norwegian Univ Sci & Technol, Norway; SINTEF AS, Norway.
    Wideroe, Marius
    Norwegian Univ Sci & Technol, Norway.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Lars N. G.
    Univ Oslo, Norway; Oslo Univ Hosp, Norway.
    Davies, Catharina de Lange
    Norwegian Univ Sci & Technol, Norway.
    Aslund, Andreas K. O.
    Norwegian Univ Sci & Technol, Norway; SINTEF AS, Norway.
    Contrast Enhanced Magnetic Resonance Imaging of Amyloid-beta Plaques in a Murine Alzheimers Disease Model2023In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 93, no 2, p. 411-419Article in journal (Refereed)
    Abstract [en]

    Background: Early detection of amyloid-beta(A beta) aggregates is a critical step to improve the treatment of Alzheimers disease (AD) because neuronal damage by the A beta aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of A beta, can be used to fluorescently label amyloid plaque in living rodents. Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T-1-weighted magnetic resonance imaging (MRI). Methods: A novel LCO-gadolinium construct was synthesized to selectively bind to A beta plaques and give contrast in conventional T-1-weighted MR images after intravenous injection in Tg-APPSwe mice. Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI. Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection.

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  • 8.
    Björk, Linnea
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Todarwal, Yogesh
    KTH Royal Inst Technol, Sweden.
    Linares, Mathieu
    KTH Royal Inst Technol, Sweden.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, K. Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Distinct Heterocyclic Moieties Govern the Selectivity of Thiophene-Vinylene-Based Ligands towards Aß or Tau Pathology in Alzheimer's Disease2023In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 26, no 41, article id e202300583Article in journal (Refereed)
    Abstract [en]

    Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene-based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheimers disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid-beta (A beta), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene-vinylene building block displayed selectivity to aggregated A beta pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD.

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  • 9.
    Torre-Muruzabal, Teresa
    et al.
    KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
    Van der Perren, Anke
    KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
    Coens, Audrey
    Institut François Jacob (MIRCen), CEA, and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France.
    Gelders, Géraldine
    KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
    Janer, Anna Barber
    KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
    Camacho-Garcia, Sara
    KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Stefanova, Nadia
    Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
    Melki, Ronald
    Institut François Jacob (MIRCen), CEA, and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France.
    Baekelandt, Veerle
    KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
    Peelaerts, Wouter
    KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
    Host oligodendrogliopathy and ɑ-synuclein strains dictate disease severity in multiple system atrophy2023In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 1, p. 237-251Article in journal (Refereed)
    Abstract [en]

    Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages different subtypes of multiple system atrophy are distinguished by their predominant parkinsonian or cerebellar symptoms reflecting the heterogeneous nature of the disease. The pathognomonic feature of multiple system atrophy is the presence of ɑ-synuclein (ɑSyn) protein deposits in oligodendroglial cells. ɑSyn can assemble in specific cellular or disease environments and form ɑSyn strains with unique structural features but the ability of ɑSyn strains to propagate in oligodendrocytes remains elusive. More recently, it was shown that multiple multiple system atrophy strains with related conformations exist in the brain of patients. Here, we investigated if different ɑSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant ɑSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that ɑSyn protein strains determine disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. ɑSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of ɑSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagate oligodendroglial inclusions that are structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions in multiple system atrophy patient brain. This study therefore shows that the multiple system atrophy phenotype is governed by both the ɑSyn strain nature and the host environment and that by injecting ɑSyn strains in a multiple system atrophy animal model a more comprehensive phenotype can be established.

  • 10.
    Ilkhanizadeh, Shirin
    et al.
    Karolinska Inst, Sweden.
    Gracias, Aileen
    Karolinska Inst, Sweden.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bäck, Markus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kavanagh, Edel
    Karolinska Inst, Sweden.
    Migliori, Bianca
    Karolinska Inst, Sweden.
    Neofytou, Christina
    Karolinska Inst, Sweden.
    Nelander, Sven
    Uppsala Univ, Sweden.
    Westermark, Bengt
    Uppsala Univ, Sweden.
    Uhrbom, Lene
    Uppsala Univ, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala Univ, Sweden.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Teixeira, Ana I.
    Karolinska Inst, Sweden.
    Uhlen, Per
    Karolinska Inst, Sweden.
    Joseph, Bertrand
    Karolinska Inst, Sweden.
    Hermanson, Ola
    Karolinska Inst, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Live Detection of Neural Progenitors and Glioblastoma Cells by an Oligothiophene Derivative2023In: ACS Applied Bio Materials, E-ISSN 2576-6422, Vol. 6, no 9, p. 3790-3797Article in journal (Refereed)
    Abstract [en]

    There is an urgent need for simple and non-invasive identification of live neural stem/progenitor cells (NSPCs) in the developing and adult brain as well as in disease, such as in brain tumors, due to the potential clinical importance in prognosis, diagnosis, and treatment of diseases of the nervous system. Here, we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) stem cell-like cells and NSPCs. While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSPCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same cell population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of neural and glioma stem and progenitor cells.

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  • 11.
    Aguilar-Calvo, Patricia
    et al.
    Univ Calif San Diego, CA 92093 USA; Pfizer, CA USA.
    Malik, Adela
    Univ Calif San Diego, CA 92093 USA; Fate Therapeut, CA USA.
    Sandoval, Daniel R.
    Univ Calif San Diego, CA USA; GSK plc, PA USA.
    Barback, Christopher
    Univ Calif San Diego, CA USA; Univ Colorado, CO USA.
    Orru, Christina D.
    NIAID, MT USA.
    Standke, Heidi G.
    Case Western Reserve Univ, OH USA.
    Thomas, Olivia R.
    Case Western Reserve Univ, OH USA.
    Dwyer, Chrissa A.
    Univ Calif San Diego, CA USA.
    Pizzo, Donald P.
    Univ Calif San Diego, CA 92093 USA.
    Bapat, Jaidev
    Univ Calif San Diego, CA 92093 USA.
    Soldau, Katrin
    Univ Calif San Diego, CA 92093 USA.
    Ogawa, Ryotaro
    Univ Calif San Diego, CA USA.
    Riley, Mckenzie B.
    Univ Alabama Birmingham, AL USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kraus, Allison
    Case Western Reserve Univ, OH USA.
    Caughey, Byron
    NIAID, MT USA.
    Iliff, Jeffrey J.
    VA Puget Sound Hlth Care Syst, WA USA; Univ Washington, WA USA.
    Vera, David R.
    Univ Calif San Diego, CA USA.
    Esko, Jeffrey D.
    Univ Calif San Diego, CA USA.
    Sigurdson, Christina J.
    Univ Calif San Diego, CA 92093 USA; UC San Diego Hlth, CA 92093 USA; Bristol Myers Squibb, CA USA.
    Neuronal Ndst1 depletion accelerates prion protein clearance and slows neurodegeneration in prion infection2023In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 9, article id e1011487Article in journal (Refereed)
    Abstract [en]

    Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a major extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase), from neurons or astrocytes, we then investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, only affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of mice expressing unsulfated HS, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance. Prions cause a rapidly progressive neurologic disease and death with no curative treatment available. Prion aggregates accumulate exponentially in the brain of affected individuals triggering neuronal loss and neuroinflammation, yet the molecules that facilitate prion protein aggregation are largely unknown. We have found that prions in the brain preferentially bind to a highly sulfated endogenous polysaccharide, known as heparan sulfate (HS). Here we use genetically modified mice that express poorly sulfated, neuron-derived HS, and infect mice with different prions strains. We find that mice infected with a plaque-forming prion strain show a prolonged survival and fewer plaques compared to controls. We also found that recombinant prion protein was efficiently transported within the interstitial fluid of mice having poorly sulfated HS, suggesting more efficient clearance from the brain. Our study provides insight into how HS retains prion aggregates in the brain to accelerate disease and indicates a specific HS biosynthetic enzyme to target to enhance protein clearance.

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  • 12.
    Hageberg, Ingvild U.
    et al.
    Norwegian Univ Sci & Technol, Norway.
    Arja, Katrianne
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Vindstad, Benedikte E.
    Norwegian Univ Sci & Technol, Norway.
    Bergvoll, Johannes K.
    Norwegian Univ Sci & Technol, Norway.
    Gederaas, Odrun A.
    Univ Agder, Norway.
    Melo, Thor-Bernt
    Norwegian Univ Sci & Technol, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Photophysics of Glycosylated Ring-Fused Chlorin Complexes and Their Photosensitizing Effects on Cancer Cells2023In: ChemPhotoChem, E-ISSN 2367-0932, Vol. 7, no 8, article id e202300028Article in journal (Refereed)
    Abstract [en]

    The future of photodynamic therapy (PDT) as a promising cancer treatment relies on the development of new selective and effective photosensitizers (PS) with improved photophysical and biochemical qualities. Herein, we present the synthetic procedure, photophysical properties and photosensitizing effects of novel glycosylated 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine] fused chlorin agents featuring either glucose, galactose, or N-acetyl glucosamine. It is shown that both the proto- and Zn2+-ion forms of the ring-stabilized glycochlorins exhibit the required photophysical properties in terms of triplet excited states and singlet oxygen generation, the latter more than 50 % in organic solvents such as CHCl3. Employing the rat AY-27 and human T24 cancer cell models, it was found that these are superior to the corresponding unglycosylated chlorin in biological activity, and moreover, the proto form is 2-3 times superior to the Zn-stabilized variant. Provisional flow cytometry and cell localization studies of the proto-form indicate both necrotic and apoptotic biological activity, and that the photosensitizer localizes in the mitochondria, cell membrane and lysosomes. However, the localization into the lysosomes is dominating and increases substantially with time. We anticipate the findings will aid in the development of photosensitizers for targeted cancer PDT.

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  • 13.
    Arja, Katriann
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Paloncyova, Marketa
    KTH Royal Inst Technol, Sweden; Palacky Univ Olomouc, Czech Republic.
    Linares, Mathieu
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Self-Assembly of Chiro-Optical Materials from Nonchiral Oligothiophene-Porphyrin Derivatives and Random Coil Synthetic Peptides2023In: ChemPlusChem, E-ISSN 2192-6506, Vol. 88, no 1Article in journal (Refereed)
    Abstract [en]

    Biomimetic chiral optoelectronic materials can be utilized in electronic devices, biosensors and artificial enzymes. Herein, this work reports the chiro-optical properties and architectural arrangement of optoelectronic materials generated from self-assembly of initially nonchiral oligothiophene-porphyrin derivatives and random coil synthetic peptides. The photo-physical- and structural properties of the materials were assessed by absorption-, fluorescence- and circular dichroism spectroscopy, as well as dynamic light scattering, scanning electron microscopy and theoretical calculations. The materials display a three-dimensional ordered helical structure and optical activity that are observed due to an induced chirality of the optoelectronic element upon interaction with the peptide. Both these properties are influenced by the chemical composition of the oligothiophene-porphyrin derivative, as well as the peptide sequence. We foresee that our findings will aid in developing self-assembled optoelectronic materials with dynamic architectonical accuracies, as well as offer the possibility to generate the next generation of materials for a variety of bioelectronic applications.

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  • 14.
    Björk, Linnea
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thiophene-Based Ligands: Design, Synthesis and Their Utilization for Optical Assignment of Polymorphic-Disease-Associated Protein Aggregates2023In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 24, article id e202300044Article, review/survey (Refereed)
    Abstract [en]

    The development of ligands for detecting protein aggregates is of great interest, as these aggregated proteinaceous species are the pathological hallmarks of several devastating diseases, including Alzheimers disease. In this regard, thiophene-based ligands have emerged as powerful tools for fluorescent assessment of these pathological entities. The intrinsic conformationally sensitive photophysical properties of poly- and oligothiophenes have allowed optical assignment of disease-associated protein aggregates in tissue sections, as well as real-time in vivo imaging of protein deposits. Herein, we recount the chemical evolution of different generations of thiophene-based ligands, and exemplify their use for the optical distinction of polymorphic protein aggregates. Furthermore, the chemical determinants for achieving a superior fluorescent thiophene-based ligand, as well as the next generation of thiophene-based ligands targeting distinct aggregated species are described. Finally, the directions for future research into the chemical design of thiophene-based ligands that can aid in resolving the scientific challenges around protein aggregation diseases are discussed.

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  • 15.
    Lantz, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thiophene-Based Ligands for Histological Multiplex Spectral Detection of Distinct Protein Aggregates in Alzheimers Disease2023In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, article id e202203568Article in journal (Refereed)
    Abstract [en]

    The aggregation and accumulation of proteins in the brain is the defining feature of many devastating neurodegenerative diseases. The development of fluorescent ligands that bind to these accumulations, or deposits, is essential for the characterization of these neuropathological lesions. We report the synthesis of donor-acceptor-donor (D-A-D) thiophene-based ligands with different emission properties. The D-A-D ligands displayed selectivity towards distinct disease-associated protein deposits in histological sections from postmortem brain tissue of individuals affected by Alzheimers disease (AD). The ability of the ligands to selectively identify AD-associated pathological alterations, such as deposits composed of aggregates of the amyloid-beta (A beta) peptide or tau, was reduced when the chemical composition of the ligands was altered. When combining the D-A-D ligands with conventional thiophene-based ligands, superior spectral separation of distinct protein aggregates in AD tissue sections was obtained. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species, as well as offer novel strategies for developing multiplex fluorescence detection of protein aggregates in tissue sections.

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  • 16.
    Gomez-Gutierrez, Ruben
    et al.
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA; Univ Malaga, Spain.
    Ghosh, Ujjayini
    Natl Inst Diabet & Digest & Kidney Dis, MD 20892 USA.
    Yau, Wai-Ming
    Natl Inst Diabet & Digest & Kidney Dis, MD 20892 USA.
    Gamez, Nazaret
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA; Univ Malaga, Spain.
    Do, Katherine
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    Kramm, Carlos
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Vegas-Gomez, Laura
    Univ Malaga, Spain.
    Schulz, Jonathan
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    Moreno-Gonzalez, Ines
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA; Univ Malaga, Spain; Ctr Invest Biomed Red Enfermedades Neurodegenerat, Spain; Univ Bernardo OHiggins, Chile.
    Gutierrez, Antonia
    Univ Malaga, Spain; Ctr Invest Biomed Red Enfermedades Neurodegenerat, Spain.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Tycko, Robert
    Natl Inst Diabet & Digest & Kidney Dis, MD 20892 USA.
    Soto, Claudio
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    Morales, Rodrigo
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA; Univ Bernardo OHiggins, Chile.
    Two structurally defined A & beta; polymorphs promote different pathological changes in susceptible mice2023In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 24, no 8, article id e57003Article in journal (Refereed)
    Abstract [en]

    Misfolded A & beta; is involved in the progression of Alzheimers disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded A & beta; strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain-specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, tropism to specific brain regions, differential recruitment of A & beta;(40)/A & beta;(42) peptides, and induction of microglial and astroglial responses. Importantly, the aggregates induced by 2F and 3F are structurally different as determined by ssNMR. Our study analyzes the biological properties of purified A & beta; polymorphs that have been characterized at the atomic resolution level and provides relevant information on the pathological significance of misfolded A & beta; strains.

  • 17.
    Kirschenbaum, Daniel
    et al.
    Univ Zurich, Switzerland.
    Dadgar-Kiani, Ehsan
    Stanford Univ, CA 94305 USA.
    Catto, Francesca
    Univ Zurich, Switzerland.
    Voigt, Fabian F.
    Univ Zurich, Switzerland; Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland.
    Trevisan, Chiara
    Univ Zurich, Switzerland.
    Bichsel, Oliver
    Univ Zurich, Switzerland.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Frontzek, Karl J.
    Univ Zurich, Switzerland.
    Paganetti, Paolo
    Ente Cantonale Osped, Switzerland; Univ Svizzera Italiana, Switzerland.
    Helmchen, Fritjof
    Univ Zurich, Switzerland.
    Lee, Jin Hyung
    Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA; Stanford Univ, CA 94305 USA.
    Aguzzi, Adriano
    Univ Zurich, Switzerland.
    Whole-brain microscopy reveals distinct temporal and spatial efficacy of anti-A beta therapies2023In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 15, article id e16789Article in journal (Refereed)
    Abstract [en]

    Many efforts targeting amyloid-beta (A beta) plaques for the treatment of Alzheimers Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-A beta treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to beta-secretase inhibitors, polythiophenes, or anti-A beta antibodies. Each treatment showed unique spatiotemporal A beta clearance, with polythiophenes emerging as a potent anti-A beta compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each A beta therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of A beta plaques. This may also contribute to the clinical trial failures of A beta-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.

  • 18.
    Just, Mie Kristine
    et al.
    Aarhus Univ, Denmark; Aarhus Univ Hosp, Denmark.
    Gram, Hjalte
    Aarhus Univ, Denmark.
    Theologidis, Vasileios
    Aarhus Univ, Denmark.
    Jensen, Poul Henning
    Aarhus Univ, Denmark.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Knudsen, Karoline
    Aarhus Univ, Denmark; Aarhus Univ Hosp, Denmark.
    Borghammer, Per
    Aarhus Univ, Denmark; Aarhus Univ Hosp, Denmark.
    van den Berge, Nathalie
    Aarhus Univ, Denmark; Aarhus Univ Hosp, Denmark.
    Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies2022In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 14, article id 907293Article, review/survey (Refereed)
    Abstract [en]

    Pathogenic alpha-synuclein (asyn) aggregates are a defining feature of neurodegenerative synucleinopathies, which include Parkinsons disease, Lewy body dementia, pure autonomic failure and multiple system atrophy. Early accurate differentiation between these synucleinopathies is challenging due to the highly heterogeneous clinical profile at early prodromal disease stages. Therefore, diagnosis is often made in late disease stages when a patient presents with a broad range of motor and non-motor symptoms easing the differentiation. Increasing data suggest the clinical heterogeneity seen in patients is explained by the presence of distinct asyn strains, which exhibit variable morphologies and pathological functions. Recently, asyn seed amplification assays (PMCA and RT-QuIC) and conformation-specific ligand assays have made promising progress in differentiating between synucleinopathies in prodromal and advanced disease stages. Importantly, the cellular environment is known to impact strain morphology. And, asyn aggregate pathology can propagate trans-synaptically along the brain-body axis, affecting multiple organs and propagating through multiple cell types. Here, we present our hypothesis that the changing cellular environments, an asyn seed may encounter during its brain-to-body or body-to-brain propagation, may influence the structure and thereby the function of the aggregate strains developing within the different cells. Additionally, we aim to review strain characteristics of the different synucleinopathies in clinical and preclinical studies. Future preclinical animal models of synucleinopathies should investigate if asyn strain morphology is altered during brain-to-body and body-to-brain spreading using these seeding amplification and conformation-specific assays. Such findings would greatly deepen our understanding of synucleinopathies and the potential link between strain and phenotypic variability, which may enable specific diagnosis of different synucleinopathies in the prodromal phase, creating a large therapeutic window with potential future applications in clinical trials and personalized therapeutics.

  • 19.
    Wennström, Malin
    et al.
    Lund Univ, Sweden.
    Janelidze, Shorena
    Lund Univ, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Serrano, Geidy E.
    Eli Lilly & Co, IN USA.
    Beach, Thomas G.
    Eli Lilly & Co, IN USA.
    Dage, Jeffrey L.
    Indiana Univ Sch Med, IN USA; Skane Univ Hosp, Sweden.
    Hansson, Oskar
    Lund Univ, Sweden.
    Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels2022In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 10, no 1, article id 3Article in journal (Refereed)
    Abstract [en]

    Recent studies highlight phosphorylated tau (p-tau) at threonine tau 217 (p-tau217) as a new promising plasma biomarker for pathological changes implicated in Alzheimers disease (AD), but the specific brain pathological events related to the alteration in p-tau217 plasma levels are still largely unknown. Using immunostaining techniques of postmortem AD brain tissue, we show that p-tau217 is found in neurofibrillary tangles (NFTs) and neuropil threads that are also positive for p-tau181, 202, 202/205, 231, and 369/404. The p-tau217, but not the other five p-tau variants, was also prominently seen in vesicles structure positive for markers of granulovacuolar degeneration bodies and multi-vesicular bodies. Further, individuals with a high likelihood of AD showed significantly higher p-tau217 area fraction in 4 different brain areas (entorhinal cortex, inferior temporal gyrus, and superior frontal gyrus) compared to those with Primary age related tauopathy or other non-AD tauopathies. The p-tau217 area fraction correlated strongly with total amyloid-beta (A beta) and NFT brain load when the whole group was analyzed. Finally, the mean p-tau217 area fraction correlated significantly with p-tau217 concentrations in antemortem collected plasma specifically in individuals with amyloid plaques and not in those without amyloid plaques. These studies highlight differences in cellular localization of different p-tau variants and suggest that plasma levels of p-tau217 reflect an accumulation of p-tau217 in presence of A beta plaque load.

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  • 20.
    Lerouge, Frederic
    et al.
    Univ Lyon 1, France.
    Ong, Elodie
    Univ Lyon 1, France.
    Rositi, Hugo
    Univ Clermont Auvergne, France.
    Mpambani, Francis
    Univ Lyon 1, France.
    Berner, Lise-Prune
    Univ Lyon 1, France.
    Bolbos, Radu
    CERMEP, France.
    Olivier, Cecile
    Univ Lyon 1, France.
    Peyrin, Francoise
    Univ Lyon 1, France.
    Apputukan, Vinu K.
    Univ Lyon 1, France.
    Monnereau, Cyrille
    Univ Lyon 1, France.
    Andraud, Chantal
    Univ Lyon 1, France.
    Chaput, Frederic
    Univ Lyon 1, France.
    Berthezene, Yves
    Univ Lyon 1, France.
    Braun, Bettina
    Univ Tubingen, Germany.
    Jucker, Mathias
    Univ Tubingen, Germany.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. SINTEF Ind, Norway.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Wiart, Marlene
    Univ Lyon, France; CNRS, France.
    Chauveau, Fabien
    Univ Lyon 1, France.
    Parola, Stephane
    Univ Lyon 1, France.
    In vivo targeting and multimodal imaging of cerebral amyloid-beta aggregates using hybrid GdF3 nanoparticles2022In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 17, no 29, p. 2173-2187Article in journal (Refereed)
    Abstract [en]

    Aim: To propose a new multimodal imaging agent targeting amyloid-beta (A beta) plaques in Alzheimers disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimers disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful A beta targeting in both transgenic mice and A beta fibril-injected rats.

  • 21.
    Wagner, Jessica
    et al.
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Tubingen, Germany.
    Degenhardt, Karoline
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Tubingen, Germany.
    Veit, Marleen
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Tubingen, Germany.
    Louros, Nikolaos
    VIB KU Leuven Ctr Brain & Dis Res, Belgium; Katholieke Univ Leuven, Belgium.
    Konstantoulea, Katerina
    VIB KU Leuven Ctr Brain & Dis Res, Belgium; Katholieke Univ Leuven, Belgium.
    Skodras, Angelos
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Wild, Katleen
    German Ctr Neurodegenerat Dis DZNE, Germany.
    Liu, Ping
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Tubingen, Germany.
    Obermueller, Ulrike
    Univ Tubingen, Germany.
    Bansal, Vikas
    German Ctr Neurodegenerat Dis DZNE, Germany.
    Dalmia, Anupriya
    German Ctr Neurodegenerat Dis DZNE, Germany.
    Haesler, Lisa M.
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Lambert, Marius
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    De Vleeschouwer, Matthias
    VIB KU Leuven Ctr Brain & Dis Res, Belgium; Katholieke Univ Leuven, Belgium.
    Davies, Hannah A.
    Univ Liverpool, England; Univ Liverpool, England.
    Madine, Jillian
    Univ Liverpool, England; Univ Liverpool, England.
    Kronenberg-Versteeg, Deborah
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Feederle, Regina
    Helmholtz Zentrum Munchen, Germany; German Ctr Neurodegenerat Dis DZNE, Germany.
    Del Turco, Domenico
    Goethe Univ, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lashley, Tammaryn
    UCL, England; UCL, England.
    Deller, Thomas
    Goethe Univ, Germany.
    Gearing, Marla
    Emory Univ, GA 30322 USA; Emory Univ, GA 30322 USA.
    Walker, Lary C.
    Emory Univ, GA 30322 USA; Emory Univ, GA 30322 USA.
    Heutink, Peter
    German Ctr Neurodegenerat Dis DZNE, Germany.
    Rousseau, Frederic
    VIB KU Leuven Ctr Brain & Dis Res, Belgium; Katholieke Univ Leuven, Belgium.
    Schymkowitz, Joost
    VIB KU Leuven Ctr Brain & Dis Res, Belgium; Katholieke Univ Leuven, Belgium.
    Jucker, Mathias
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Neher, Jonas J.
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Medin co-aggregates with vascular amyloid-beta in Alzheimers disease2022In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 612, p. 123-131Article in journal (Refereed)
    Abstract [en]

    Aggregates of medin amyloid (a fragment of the protein MFG-E8, also known as lactadherin) are found in the vasculature of almost all humans over 50 years of age(1,)(2), making it the most common amyloid currently known. We recently reported that medin also aggregates in blood vessels of ageing wild-type mice, causing cerebrovascular dysfunction(3). Here we demonstrate in amyloid-beta precursor protein (APP) transgenic mice and in patients with Alzheimers disease that medin co-localizes with vascular amyloid-beta deposits, and that in mice, medin deficiency reduces vascular amyloid-beta deposition by half. Moreover, in both the mouse and human brain, MFG-E8 is highly enriched in the vasculature and both MFG-E8 and medin levels increase with the severity of vascular amyloid-beta burden. Additionally, analysing data from 566 individuals in the ROSMAP cohort, we find that patients with Alzheimers disease have higher MFGE8 expression levels, which are attributable to vascular cells and are associated with increased measures of cognitive decline, independent of plaque and tau pathology. Mechanistically, we demonstrate that medin interacts directly with amyloid-beta to promote its aggregation, as medin forms heterologous fibrils with amyloid-beta, affects amyloid-beta fibril structure, and cross-seeds amyloid-beta aggregation both in vitro and in vivo. Thus, medin could be a therapeutic target for prevention of vascular damage and cognitive decline resulting from amyloid-beta deposition in the blood vessels of the brain.

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  • 22.
    Ni, Ruiqing
    et al.
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Chen, Zhenyue
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland.
    Dean-Ben, Xose Luis
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland.
    Voigt, Fabian F.
    Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Kirschenbaum, Daniel
    Univ Spital Zurich, Switzerland.
    Shi, Gloria
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland.
    Villois, Alessia
    Swiss Fed Inst Technol, Switzerland.
    Zhou, Quanyu
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland.
    Crimi, Alessandro
    Univ Spital Zurich, Switzerland.
    Arosio, Paolo
    Swiss Fed Inst Technol, Switzerland.
    Nitsch, Roger M.
    Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Aguzzi, Adriano
    Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Spital Zurich, Switzerland.
    Helmchen, Fritjof
    Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Klohs, Jan
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland.
    Razansky, Daniel
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Multiscale optical and optoacoustic imaging of amyloid-beta deposits in mice2022In: Nature Biomedical Engineering, E-ISSN 2157-846X, Vol. 6, p. 1031-1044Article in journal (Refereed)
    Abstract [en]

    Large-field multifocal illumination fluorescence microscopy and panoramic volumetric multispectral optoacoustic tomography can be combined to longitudinally assess amyloid-beta deposits in transgenic mouse models of Alzheimers disease. Deposits of amyloid-beta (A beta) in the brains of rodents can be analysed by invasive intravital microscopy on a submillimetre scale, or via whole-brain images from modalities lacking the resolution or molecular specificity to accurately characterize A beta pathologies. Here we show that large-field multifocal illumination fluorescence microscopy and panoramic volumetric multispectral optoacoustic tomography can be combined to longitudinally assess A beta deposits in transgenic mouse models of Alzheimers disease. We used fluorescent A beta-targeted probes (the luminescent conjugated oligothiophene HS-169 and the oxazine-derivative AOI987) to transcranially detect A beta deposits in the cortex of APP/PS1 and arcA beta mice with single-plaque resolution (8 mu m) and across the whole brain (including the hippocampus and the thalamus, which are inaccessible by conventional intravital microscopy) at sub-150 mu m resolutions. Two-photon microscopy, light-sheet microscopy and immunohistochemistry of brain-tissue sections confirmed the specificity and regional distributions of the deposits. High-resolution multiscale optical and optoacoustic imaging of A beta deposits across the entire brain in rodents thus facilitates the in vivo study of A beta accumulation by brain region and by animal age and strain.

  • 23.
    Björk, Linnea
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lantz, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Proteophenes - Amino Acid Functionalized Thiophene-based Fluorescent Ligands for Visualization of Protein Deposits in Tissue Sections with Alzheimers Disease Pathology2022In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 62, article id e202201557Article in journal (Refereed)
    Abstract [en]

    Protein deposits composed of specific proteins or peptides are associated with several neurodegenerative diseases and fluorescent ligands able to detect these pathological hallmarks are vital. Here, we report the synthesis of a class of thiophene-based ligands, denoted proteophenes, with different amino acid side-chain functionalities along the conjugated backbone, which display selectivity towards specific disease-associated protein aggregates in tissue sections with Alzheimers disease (AD) pathology. The selectivity of the ligands towards AD associated pathological hallmarks, such as aggregates of the amyloid-beta (A beta) peptide or tau filamentous inclusions, was highly dependent on the chemical nature of the amino acid functionality, as well as on the location of the functionality along the pentameric thiophene backbone. Finally, the concept of synthesizing donor-acceptor-donor proteophenes with distinct photophysical properties was shown. Our findings provide the structural and functional basis for the development of new thiophene-based ligands that can be utilized for optical assignment of different aggregated proteinaceous species in tissue sections.

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  • 24.
    Butina, Karen
    et al.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Lantz, Linda
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Choong, Ferdinand X.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Tomac, Ana
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Löffler, Susanne
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Structural Properties Dictating Selective Optotracer Detection of Staphylococcus aureus2022In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 23, no 11, article id e202100684Article in journal (Refereed)
    Abstract [en]

    Optotracers are conformation-sensitive fluorescent tracer molecules that detect peptide- and carbohydrate-based biopolymers. Their binding to bacterial cell walls allows selective detection and visualisation of Staphylococcus aureus (S. aureus). Here, we investigated the structural properties providing optimal detection of S. aureus. We quantified spectral shifts and fluorescence intensity in mixes of bacteria and optotracers, using automatic peak analysis, cross-correlation, and area-under-curve analysis. We found that the length of the conjugated backbone and the number of charged groups, but not their distribution, are important factors for selective detection of S. aureus. The photophysical properties of optotracers were greatly improved by incorporating a donor-acceptor-donor (D-A-D)-type motif in the conjugated backbone. With significantly reduced background and binding-induced on-switch of fluorescence, these optotracers enabled real-time recordings of S. aureus growth. Collectively, this demonstrates that chemical structure and photophysics are key tunable characteristics in the development of optotracers for selective detection of bacterial species.

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  • 25.
    Faustini, Gaia
    et al.
    Univ Brescia, Italy.
    Longhena, Francesca
    Univ Brescia, Italy.
    Masato, Anna
    Univ Padua, Italy.
    Bassareo, Valentina
    Univ Cagliari, Italy.
    Frau, Roberto
    Univ Cagliari, Italy.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brembati, Viviana
    Univ Brescia, Italy.
    Parrella, Edoardo
    Univ Brescia, Italy.
    Vezzoli, Marika
    Univ Brescia, Italy.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Pizzi, Marina
    Univ Brescia, Italy.
    Spillantini, Maria Grazia
    Univ Cambridge, England.
    Bubacco, Luigi
    Univ Padua, Italy.
    Bellucci, Arianna
    Univ Brescia, Italy.
    Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinsons disease-like phenotype2022In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 30, no 4, p. 1465-1483Article in journal (Refereed)
    Abstract [en]

    Fibrillary aggregated alpha-synuclein (alpha-syn) deposition in Lewy bodies (LB) characterizes Parkinsons disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with alpha-syn to regulate dopamine (DA) release and can be found in the insoluble alpha-syn fibrils composing LB. Moreover, we showed that a-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human alpha-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates alpha-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human alpha-syn transgenic mice at PD-like stage with advanced alpha-syn aggregation and overt striatal synaptic failure, we could lower alpha-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates alpha-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.

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  • 26.
    Ruiz-Riquelme, Alejandro
    et al.
    Univ Toronto, Canada; UCL, England.
    Mao, Alison
    Univ Toronto, Canada; Univ Toronto, Canada.
    Barghash, Marim M.
    Univ Toronto, Canada; Univ Toronto, Canada.
    Lau, Heather H. C.
    Univ Toronto, Canada; Univ Toronto, Canada.
    Stuart, Erica
    Univ Toronto, Canada.
    Kovacs, Gabor G.
    Univ Toronto, Canada; Univ Toronto, Canada; Univ Hlth Network, Canada; Univ Hlth Network, Canada.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Fraser, Paul E.
    Univ Toronto, Canada; Univ Toronto, Canada.
    Schmitt-Ulms, Gerold
    Univ Toronto, Canada; Univ Toronto, Canada.
    Watts, Joel C.
    Univ Toronto, Canada; Univ Toronto, Canada.
    A beta 43 aggregates exhibit enhanced prion-like seeding activity in mice2021In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 9, no 1, article id 83Article in journal (Refereed)
    Abstract [en]

    When injected into genetically modified mice, aggregates of the amyloid-beta (A beta) peptide from the brains of Alzheimers disease (AD) patients or transgenic AD mouse models seed cerebral A beta deposition in a prion-like fashion. Within the brain, A beta exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal A beta variants to the seeding behavior of A beta aggregates remains unknown. Here, we have investigated the relative seeding activities of A beta aggregates composed exclusively of recombinant A beta 38, A beta 40, A beta 42, or A beta 43. Cerebral A beta 42 levels were not increased in App(NL-F) knock-in mice injected with A beta 38 or A beta 40 aggregates and were only increased in a subset of mice injected with A beta 42 aggregates. In contrast, significant accumulation of A beta 42 was observed in the brains of all mice inoculated with A beta 43 aggregates, and the extent of A beta 42 induction was comparable to that in mice injected with brain-derived A beta seeds. Mice inoculated with A beta 43 aggregates exhibited a distinct pattern of cerebral A beta pathology compared to mice injected with brain-derived A beta aggregates, suggesting that recombinant A beta 43 may polymerize into a unique strain. Our results indicate that aggregates containing longer A beta C-terminal variants are more potent inducers of cerebral A beta deposition and highlight the potential role of A beta 43 seeds as a crucial factor in the initial stages of A beta pathology in AD.

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  • 27.
    Reyes, Juan
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekmark-Lewen, Sara
    Uppsala Univ, Sweden.
    Perdiki Grigoriadi, Marina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Hoffmann, Alana
    Friedrich Alexander Univ Erlangen Nurnberg, Germany.
    Wiechec, Emilia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Per
    Karolinska Inst, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Alafuzoff, Irina
    Uppsala Univ Hosp, Sweden.
    Ingelsson, Martin
    Uppsala Univ, Sweden.
    Hallbeck, Martin
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinsons disease2021In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 9, no 1, article id 46Article in journal (Refereed)
    Abstract [en]

    Alpha-synuclein (alpha-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinsons disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that alpha-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that alpha-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric alpha-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of alpha-syn within the liver of three different transgenic (tg) mouse models expressing human alpha-syn under CNS-specific promoters, despite the lack of alpha-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of alpha-syn pathology within the liver of wild type mice one month after a single striatal alpha-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Ass) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed alpha-syn pathology containing alpha-syn within hepatocellular structures to a higher degree (75%) than control subjects without alpha-syn accumulation in the brain (57%). Our results reveal that alpha-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.

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  • 28.
    Gustafsson, Camilla
    et al.
    KTH Royal Inst Technol, Sweden.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Leira, Petter
    Norwegian Univ Sci & Technol NTNU, Norway.
    Rehn, Dirk R.
    KTH Royal Inst Technol, Sweden.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering. KTH Royal Inst Technol, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol NTNU, Norway.
    Deciphering the Electronic Transitions of Thiophene-Based Donor-Acceptor-Donor Pentameric Ligands Utilized for Multimodal Fluorescence Microscopy of Protein Aggregates2021In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 22, no 3, p. 323-335Article in journal (Refereed)
    Abstract [en]

    Anionic pentameric thiophene acetates can be used for fluorescence detection and diagnosis of protein amyloid aggregates. Replacing the central thiophene unit by benzothiadiazole (BTD) or quinoxaline (QX) leads to large emission shifts and basic spectral features have been reported [Chem. Eur. J. 2015, 21, 15133-13137]. Here we present new detailed experimental results of solvent effects, time-resolved fluorescence and examples employing multi-photon microscopy and lifetime imaging. Quantum chemical response calculations elucidate how the introduction of the BTD/QX groups changes the electronic states and emissions. The dramatic red-shift follows an increased conjugation and quinoid character of the pi-electrons of the thiophene backbone. An efficient charge transfer in the excited states S-1 and S-2 compared to the all-thiophene analogue makes these more sensitive to the polarity and quenching by the solvent. Taken together, the results guide in the interpretation of images of stained Alzheimer disease brain sections employing advanced fluorescence microscopy and lifetime imaging, and can aid in optimizing future fluorescent ligand development.

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  • 29.
    Liu, He
    et al.
    Case Western Reserve Univ, OH 44106 USA.
    Kim, Chae
    Case Western Reserve Univ, OH 44106 USA.
    Haldiman, Tracy
    Case Western Reserve Univ, OH 44106 USA.
    Sigurdson, Christina J.
    Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Cohen, Mark L.
    Case Western Reserve Univ, OH 44106 USA; Case Western Reserve Univ, OH USA.
    Wisniewski, Thomas
    NYU, NY USA; NYU, NY USA.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Safar, Jiri G.
    Case Western Reserve Univ, OH 44106 USA; Case Western Reserve Univ, OH 44106 USA.
    Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimers disease2021In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 297, no 5, article id 101267Article in journal (Refereed)
    Abstract [en]

    Amyloid beta (A beta) deposition in the neocortex is a major hallmark of Alzheimers disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain-like model of disease heterogeneity suggests the existence of different conformers of A beta. We explored this paradigm using conformation-dependent immunoassay (CDI) for A beta and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the A beta conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of A beta with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from A beta plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs-quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of A beta deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of A beta accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct A beta conformers (strains) in the rapid progression of AD.

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  • 30.
    Stepanchuk, Anastasiia
    et al.
    Univ Calgary, Canada.
    Tahir, Waqas
    Univ Calgary, Canada.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Schatzl, Hermann M.
    Univ Calgary, Canada.
    Stys, Peter K.
    Univ Calgary, Canada.
    Early detection of prion protein aggregation with a fluorescent pentameric oligothiophene probe using spectral confocal microscopy2021In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 156, no 6, p. 1033-1048Article in journal (Refereed)
    Abstract [en]

    Misfolding of the prion protein (PrP) and templating of its pathological conformation onto cognate proteins causes a number of lethal disorders of central nervous system in humans and animals, such as Creutzfeldt-Jacob disease, chronic wasting disease and bovine spongiform encephalopathy. Structural rearrangement of PrP (c) into PrP(Sc)promotes aggregation of misfolded proteins into beta-sheet-rich fibrils, which can be visualized by conformationally sensitive fluorescent probes. Early detection of prion misfolding and deposition might provide useful insights into its pathophysiology. Pentameric formyl thiophene acetic acid (pFTAA) is a novel amyloid probe that was shown to sensitively detect various misfolded proteins, including PrP. Here, we compared sensitivity of pFTAA staining and spectral microscopy with conventional methods of prion detection in mouse brains infected with mouse-adapted 22L prions. pFTAA bound to prion deposits in mouse brain sections exhibited a red-shifted fluorescence emission spectrum, which quantitatively increased with disease progression. Small prion deposits were detected as early as 50 days post-inoculation, well before appearance of clinical signs. Moreover, we detected significant spectral shifts in the greater brain parenchyma as early as 25 days post-inoculation, rivaling the most sensitive conventional method (real-time quaking-induced conversion). These results showcase the potential of pFTAA staining combined with spectral imaging for screening of prion-infected tissue. Not only does this method have comparable sensitivity to established techniques, it is faster and technically simpler. Finally, this readout provides valuable information about the spatial distribution of prion aggregates across tissue in the earliest stages of infection, potentially providing valuable pathophysiological insight into prion transmission.

  • 31.
    Zarb, Yvette
    et al.
    Zurich Univ, Switzerland; Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Ludwig Maximilians Univ Munchen, Germany.
    Sridhar, Sucheta
    Zurich Univ, Switzerland; Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland.
    Nassiri, Sina
    Swiss Inst Bioinformat, Switzerland.
    Utz, Sebastian Guido
    Univ Zurich, Switzerland.
    Schaffenrath, Johanna
    Zurich Univ, Switzerland; Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland.
    Maheshwari, Upasana
    Zurich Univ, Switzerland; Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland.
    Rushing, Elisabeth J.
    Zurich Univ Hosp, Switzerland.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Delorenzi, Mauro
    Swiss Inst Bioinformat, Switzerland; Univ Lausanne, Switzerland.
    Colonna, Marco
    Washington Univ, MO USA.
    Greter, Melanie
    Univ Zurich, Switzerland.
    Keller, Annika
    Zurich Univ, Switzerland; Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland.
    Microglia control small vessel calcification via TREM22021In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 9, article id eabc4898Article in journal (Refereed)
    Abstract [en]

    Microglia participate in central nervous system (CNS) development and homeostasis and are often implicated in modulating disease processes. However, less is known about the role of microglia in the biology of the neurovascular unit (NVU). In particular, data are scant on whether microglia are involved in CNS vascular pathology. In this study, we use a mouse model of primary familial brain calcification, Pdgfb(ret/ret), to investigate the role of microglia in calcification of the NVU. We report that microglia enclosing vessel calcifications, coined calcification-associated microglia, display a distinct activation phenotype. Pharmacological ablation of microglia with the CSF1R inhibitor PLX5622 leads to aggravated vessel calcification. Mechanistically, we show that microglia require functional TREM2 for controlling vascular calcification. Our results demonstrate that microglial activity in the setting of pathological vascular calcification is beneficial. In addition, we identify a previously unrecognized function of microglia in halting the expansion of vascular calcification.

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  • 32.
    Todarwal, Yogesh
    et al.
    KTH Royal Inst Technol, Sweden.
    Gustafsson, Camilla
    KTH Royal Inst Technol, Sweden.
    Minh, Nghia Nguyen Thi
    Leibniz Univ Hannover, Germany.
    Ertzgaard, Ingrid
    Norwegian Univ Sci & Technol, Norway.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    König, Carolin
    Leibniz Univ Hannover, Germany.
    Lindgren, Mikael
    Norwegian Univ Sci & Technol, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering. KTH Royal Inst Technol, Sweden.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Tau Protein Binding Modes in Alzheimers Disease for Cationic Luminescent Ligands2021In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 125, no 42, p. 11628-11636Article in journal (Refereed)
    Abstract [en]

    The bi-thiophene-vinylene-benzothiazole (bTVBT4) ligand developed for Alzheimers disease (AD)-specific detection of amyloid tau has been studied by a combination of several theoretical methods and experimental spectroscopies. With reference to the cryo-EM tau structure of the tau protofilament (Nature 2017, 547, 185), a periodic model system of the fibril was created, and the interactions between this fibril and bTVBT4 were studied with nonbiased molecular dynamics simulations. Several binding sites and binding modes were identified and analyzed, and the results for the most prevailing fibril site and ligand modes are presented. A key validation of the simulation work is provided by the favorable comparison of the theoretical and experimental absorption spectra of bTVBT4 in solution and bound to the protein. It is conclusively shown that the ligand-protein binding occurs at the hydrophobic pocket defined by the residues Ile360, Thr361, and His362. This binding site is not accessible in the Picks disease (PiD) fold, and fluorescence imaging of bTVBT4-stained brain tissue samples from patients diagnosed with AD and PiD provides strong support for the proposed tau binding site.

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  • 33.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Vidal, Ruben
    Indiana Univ Sch Med, IN 46202 USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thiophene-Based Optical Ligands That Selectively Detect A beta Pathology in Alzheimers Disease2021In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 22, no 15, p. 2568-2581Article in journal (Refereed)
    Abstract [en]

    In several neurodegenerative diseases, the presence of aggregates of specific proteins in the brain is a significant pathological hallmark; thus, developing ligands able to bind to the aggregated proteins is essential for any effort related to imaging and therapeutics. Here we report the synthesis of thiophene-based ligands containing nitrogen heterocycles. The ligands selectively recognized amyloid-beta (A beta) aggregates in brain tissue from individuals diagnosed neuropathologically as having Alzheimers disease (AD). The selectivity for A beta was dependent on the position of nitrogen in the heterocyclic compounds, and the ability to bind A beta was shown to be reduced when introducing anionic substituents on the thiophene backbone. Our findings provide the structural and functional basis for the development of ligands that can differentiate between aggregated proteinaceous species comprised of distinct proteins. These ligands might also be powerful tools for studying the pathogenesis of A beta aggregation and for designing molecules for imaging of A beta pathology.

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  • 34.
    Wahlstrom, Niklas
    et al.
    KTH Royal Inst Technol, Sweden.
    Edlund, Ulrica
    KTH Royal Inst Technol, Sweden.
    Pavia, Henrik
    Univ Gothenburg, Sweden.
    Toth, Gunilla
    Univ Gothenburg, Sweden.
    Jaworski, Aleksander
    Stockholm Univ, Sweden.
    Pell, Andrew J.
    Stockholm Univ, Sweden.
    Choong, Ferdinand X.
    Karolinska Inst, Sweden.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Sweden.
    Cellulose from the green macroalgae Ulva lactuca: isolation, characterization, optotracing, and production of cellulose nanofibrils2020In: Cellulose, ISSN 0969-0239, E-ISSN 1572-882X, Vol. 27, p. 3707-3725Article in journal (Refereed)
    Abstract [en]

    We report (1) successful extraction and characterization of cellulose from northern hemisphere green macroalgae Ulva lactuca (Ulva fenestrata) collected along the Swedish west coast and cultivated indoors under controlled conditions, followed by (2) its utilization in the production of lignin-free cellulose nanofibrils (CNF). Cellulose was extracted by sequential treatment with ethanol, hydrogen peroxide, sodium hydroxide, and hydrochloric acid, yielding a cellulose-rich insoluble fraction. The extracted cellulose was disintegrated into CNF using a mechanical homogenization process without any further enzymatic pre-treatments. In addition, regenerated cellulose was prepared. XRD characterization of the CNF showed characteristic peaks for the cellulose I allomorph and confirmed that the nanofibrils were semicrystalline with a crystallinity index of 48%. Regenerated cellulose was mostly amorphous with an XRD pattern indicating the presence of the cellulose II allomorph. The cellulose fractions were essentially free from inorganic substances and thermally stable up to around 260 degrees C. Structural mapping with CP-MAS C-13-NMR sustains the cellulose content of CNF and regenerated cellulose, respectively, yet ion chromatography identified the presence of 10-15% xylose in the fractions. Optotracing was used as a novel and non-disruptive tool to selectively assess the polysaccharide composition of the cellulose fractions and produced CNF aiming to shed light on this hitherto non-resolved origin of xylose in Ulva cell wall matter. Fluorescence excitation and emission spectra of a panel of 4 oligothiophenes identified and verified the presence of cellulose and sustain the conclusion that the isolated fractions consist of cellulose intertwined with a small amount of a xylose-containing glucan copolymer. [GRAPHICS] .

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  • 35.
    Golob-Schwarzl, N.
    et al.
    Med Univ Graz, Austria; Ctr Biomarker Res Med, Austria.
    Bettermann, K.
    Med Univ Graz, Austria.
    Mehta, A. K.
    Med Univ Graz, Austria; Dana Farber Canc Inst, MA 02215 USA.
    Kessler, S. M.
    Med Univ Graz, Austria; Saarland Univ, Germany.
    Unterluggauer, J.
    Med Univ Graz, Austria.
    Krassnig, S.
    Med Univ Graz, Austria.
    Kojima, K.
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Chen, X.
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Hoshida, Y.
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Bardeesy, N. M.
    Harvard Med Sch, MA 02115 USA.
    Mueller, H.
    Med Univ Graz, Austria.
    Svendova, V.
    Med Univ Graz, Austria.
    Schimek, M. G.
    Med Univ Graz, Austria.
    Diwoky, C.
    Graz Univ Technol, Austria; Karl Franzens Univ Graz, Austria.
    Lipfert, A.
    Ctr Biomarker Res Med, Austria; Graz Univ Technol, Austria.
    Mahajan, V.
    Med Univ Graz, Austria.
    Stumptner, C.
    Med Univ Graz, Austria.
    Thueringer, A.
    Med Univ Graz, Austria.
    Frohlich, L. F.
    Med Univ Graz, Austria; Univ Munster, Germany.
    Stojakovic, T.
    Med Univ Graz, Austria.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kolbe, T.
    Univ Vet Med Vienna, Austria; Univ Nat Resources and Appl Life Sci, Austria.
    Ruelicke, T.
    Univ Vet Med Vienna, Austria.
    Magin, T. M.
    Univ Leipzig, Germany.
    Strnad, P.
    Univ Hosp RWTH Aachen, Germany.
    Kiemer, A. K.
    Ctr Biomarker Res Med, Austria.
    Moriggl, R.
    Univ Vet Med Vienna, Austria; Ludwig Bolzmann Inst Canc Res, Austria; Med Univ Vienna, Austria.
    Haybaeck, Johannes
    Med Univ Graz, Austria; Ottovon Guericke Univ Magdeburg, Germany.
    Correction: High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype12 (vol 12, pg 256, 2019)2020In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 13, no 2, p. 490-492Article in journal (Other academic)
    Abstract [en]

    n/a

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  • 36.
    Ni, Ruiqing
    et al.
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland.
    Chen, Zhenyue
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Gerez, Juan A.
    Swiss Fed Inst Technol, Switzerland.
    Shi, Gloria
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland.
    Zhou, Quanyu
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Riek, Roland
    Swiss Fed Inst Technol, Switzerland.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Razansky, Daniel
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland; Univ Zurich, Switzerland.
    Klohs, Jan
    Univ Zurich, Switzerland; Swiss Fed Inst Technol, Switzerland; Univ Zurich, Switzerland.
    Detection of cerebral tauopathy in P301L mice using high-resolution large-field multifocal illumination fluorescence microscopy2020In: Biomedical Optics Express, E-ISSN 2156-7085, Vol. 11, no 9, p. 4989-5002Article in journal (Refereed)
    Abstract [en]

    Current intravital microscopy techniques visualize tauopathy with high-resolution, but have a small field-of-view and depth-of-focus. Herein, we report a transcranial detection of tauopathy over the entire cortex of P301L tauopathy mice using large-field multifocal illumination (LMI) fluorescence microscopy technique and luminescent conjugated oligothiophenes. In vitro assays revealed that fluorescent ligand h-FTAA is optimal for in vivo tau imaging, which was confirmed by observing elevated probe retention in the cortex of P301L mice compared to non-transgenic littermates. Immunohistochemical staining further verified the specificity of h-FTAA to detect tauopathy in P301L mice. The new imaging platform can be leveraged in pre-clinical mechanistic studies of tau spreading and clearance as well as longitudinal monitoring of tau targeting therapeutics. (C) 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

  • 37.
    Shahnawaz, Mohammad
    et al.
    Univ Texas Houston, TX 77004 USA.
    Mukherjee, Abhisek
    Univ Texas Houston, TX 77004 USA.
    Pritzkow, Sandra
    Univ Texas Houston, TX 77004 USA.
    Mendez, Nicolas
    Univ Texas Houston, TX 77004 USA.
    Rabadia, Prakruti
    Univ Texas Houston, TX 77004 USA.
    Liu, Xiangan
    Univ Texas Houston, TX USA.
    Hu, Bo
    Univ Texas Houston, TX USA.
    Schmeichel, Ann
    Mayo Clin, MN USA.
    Singer, Wolfgang
    Mayo Clin, MN USA.
    Wu, Gang
    Univ Texas Houston, TX USA.
    Tsai, Ah-Lim
    Univ Texas Houston, TX USA.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Low, Phillip A.
    Mayo Clin, MN USA.
    Soto, Claudio
    Univ Texas Houston, TX 77004 USA.
    Discriminating alpha-synuclein strains in Parkinsons disease and multiple system atrophy2020In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 578, no 7794, p. 273-277Article in journal (Refereed)
    Abstract [en]

    Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of alpha-synuclein, including Parkinsons disease, dementia with Lewy bodies and multiple system atrophy(1). Clinically, it is challenging to differentiate Parkinsons disease and multiple system atrophy, especially at the early stages of disease(2). Aggregates of alpha-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of alpha-synuclein that can self-propagate and spread from cell to cell(3-6). Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect alpha-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity(7,8). Here we show that the alpha-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinsons disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of alpha-synuclein-PMCA, and found that the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinsons disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that alpha-synuclein aggregates that are associated with Parkinsons disease and multiple system atrophy correspond to different conformational strains of alpha-synuclein, which can be amplified and detected by alpha-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of alpha-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinsons disease and multiple system atrophy. Protein misfolding cyclic amplification (PMCA) technology can discriminate between patients with Parkinsons disease and patients with multiple system atrophy on the basis of the characteristics of the alpha-synuclein aggregates in the cerebrospinal fluid.

  • 38.
    Butina, Karen
    et al.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Tomac, Ana
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Choong, Ferdinand X.
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden.
    Loffler, Susanne
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Sweden; KTH Royal Inst Technol, Sweden; Karolinska Inst, Sweden.
    Optotracing for selective fluorescence-based detection, visualization and quantification of liveS. aureusin real-time2020In: npj Biofilms and Microbiomes, E-ISSN 2055-5008, Vol. 6, no 1, article id 35Article in journal (Refereed)
    Abstract [en]

    Methods for bacterial detection are needed to advance the infection research and diagnostics. Based on conformation-sensitive fluorescent tracer molecules, optotracing was recently established for dynamic detection and visualization of structural amyloids and polysaccharides in the biofilm matrix of gram-negative bacteria. Here, we extend the use of optotracing for detection of gram-positive bacteria, focussing on the clinically relevant opportunistic human pathogenStaphylococcus aureus. We identify a donor-acceptor-donor-type optotracer, whose binding-induced fluorescence enables real-time detection, quantification, and visualization ofS. aureusin monoculture and when mixed with gram-negativeSalmonellaEnteritidis. An algorithm-based automated high-throughput screen of 1920S. aureustransposon mutants recognized the cell envelope as the binding target, which was corroborated by super-resolution microscopy of bacterial cells and spectroscopic analysis of purified cell wall components. The binding event was essentially governed by hydrophobic interactions, which permitted custom-designed tuning of the binding selectivity towardsS. aureusversusEnterococcus faecalisby appropriate selection of buffer conditions. Collectively this work demonstrates optotracing as an enabling technology relevant for any field of basic and applied research, where visualization and detection ofS. aureusis needed.

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  • 39.
    Sevillano, Alejandro M.
    et al.
    UCSD, CA USA; Univ Texas MD Anderson Canc Ctr, TX 77030 USA.
    Aguilar-Calvo, Patricia
    UCSD, CA USA.
    Kurt, Timothy D.
    UCSD, CA USA; Fdn Food and Agr Res, DC USA.
    Lawrence, Jessica A.
    UCSD, CA USA.
    Soldau, Katrin
    UCSD, CA USA.
    Nam, Thu H.
    UCSD, CA USA.
    Schumann, Taylor
    UCSD, CA USA.
    Pizzo, Donald P.
    UCSD, CA USA.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Choudhury, Biswa
    UCSD, CA USA.
    Altmeppen, Hermann
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Esko, Jeffrey D.
    UCSD, CA USA.
    Glatzel, Markus
    USD, CA USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sigurdson, Christina J.
    UCSD, CA USA.
    Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease2020In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 130, no 3, p. 1350-1362Article in journal (Refereed)
    Abstract [en]

    Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp(1)(80Q)(/196Q)), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease.Prnp(1)(80Q)(/196Q )mice challenged with 2 subfibrillar, non-plaque-forming prion strains instead developed plaques highly enriched in ADAM10-cleaved PrP and heparan sulfate (HS). Intriguingly, a third strain composed of intact, glycophosphatidylinositol-anchored (GPI-anchored) PrP was relatively unchanged, forming diffuse, HS-deficient deposits in both the Prnp(1)(80Q/196Q) and WT mice, underscoring the pivotal role of the GPI-anchor in driving the aggregate conformation and disease phenotype. Finally, knockin mice expressing triglycosylated PrP (Prnp(187N)) challenged with a plaque-forming prion strain showed a phenotype reversal, with a striking disease acceleration and switch from plaques to predominantly diffuse, subfibrillar deposits. Our findings suggest that the dominance of subfibrillar aggregates in prion disease is due to the replication of GPI-anchored prions, with fibrillar plaques forming from poorly glycosylated, GPI-anchorless prions that interact with extracellular HS. These studies provide insight into how PTMs impact PrP interactions with polyanionic cofactors, and highlight PTMs as a major force driving the prion disease phenotype.

  • 40.
    Tanrioever, Gaye
    et al.
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Bacioglu, Mehtap
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Tubingen, Germany.
    Schweighauser, Manuel
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Mahler, Jasmin
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Wegenast-Braun, Bettina M.
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Skodras, Angelos
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Obermueller, Ulrike
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Barth, Melanie
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Tubingen, Germany.
    Kronenberg-Versteeg, Deborah
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shimshek, Derya R.
    Novartis Pharma AG, Switzerland.
    Kahle, Philipp J.
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Tubingen, Germany.
    Eisele, Yvonne S.
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany; Univ Pittsburgh, PA USA.
    Jucker, Mathias
    German Ctr Neurodegenerat Dis DZNE, Germany; Univ Tubingen, Germany.
    Prominent microglial inclusions in transgenic mouse models of alpha-synucleinopathy that are distinct from neuronal lesions2020In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 8, no 1, article id 133Article in journal (Refereed)
    Abstract [en]

    Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated alpha-synuclein (alpha S). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of alpha S but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study alpha S conformers among different transgenic (TG) mouse models of alpha-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]alpha S; Thy1-h[A53T]alpha S; Thy1-h[A30P]alpha S; Thy1-m alpha S) that overexpress human or murine alpha S and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal alpha S pathology as evidenced by accumulation of alpha S serine 129 (p-alpha S) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study alpha S conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal alpha S pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of alpha S, but were largely p-alpha S-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded alpha S aggregation. Although nature and significance of microglial inclusions for human alpha-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of alpha-synucleinopathy bears importance for mechanistic and preclinical-translational studies.

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  • 41.
    Bergkvist, Liza
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Richards, Daniel R.
    Univ Cambridge, England.
    Bernardo-Gancedo, Ana
    Univ Cambridge, England.
    Kumita, Janet R.
    Univ Cambridge, England.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Serum amyloid P component promotes formation of distinct aggregated lysozyme morphologies and reduces toxicity in Drosophila flies expressing F57I lysozyme2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 1, article id e0227227Article in journal (Refereed)
    Abstract [en]

    Many conflicting reports about the involvement of serum amyloid P component (SAP) in amyloid diseases have been presented over the years; SAP is known to be a universal component of amyloid aggregates but it has been suggested that it can both induce and suppress amyloid formation. By using our Drosophila model of systemic lysozyme amyloidosis, SAP has previously been shown to reduce the toxicity induced by the expression of the disease-associated lysozyme variant, F57I, in the Drosophila central nervous system. This study further investigates the involvement of SAP in modulating lysozyme toxicity using histochemistry and spectral analyses on the double transgenic WT and F57I lysozyme flies to probe; i) formation of aggregates, ii) morphological differences of the aggregated lysozyme species formed in the presence or absence of SAP, iii) location of lysozyme and iv) co-localisation of lysozyme and SAP in the fly brain. We found that SAP can counteract the toxicity (measured by the reduction in the median survival time) induced by F57I lysozyme by converting toxic F57I species into less toxic amyloid-like structures, as reflected by the spectral changes that p-FTAA undergoes when bound to lysozyme deposits in F57I-F57I-SAP flies as compared to F57I-F57I flies. Indeed, when SAP was introduced to in vitro lysozyme fibril formation, the endpoint fibrils had enhanced ThT fluorescence intensity as compared to lysozyme fibrils alone. This suggests that a general mechanism for SAPs role in amyloid diseases may be to promote the formation of stable, amyloid-like fibrils, thus decreasing the impact of toxic species formed along the aggregation pathway.

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  • 42.
    Aguilar-Calvo, Patricia
    et al.
    Univ Calif, CA 92093 USA.
    Sevillano, Alejandro M.
    Univ Calif, CA 92093 USA.
    Bapat, Jaidev
    Univ Calif, CA 92093 USA.
    Soldau, Katrin
    Univ Calif, CA 92093 USA.
    Sandoval, Daniel R.
    Univ Calif, CA USA.
    Altmeppen, Hermann C.
    Univ Med Ctr Hamburg, Germany.
    Linsenmeier, Luise
    Univ Med Ctr Hamburg, Germany.
    Pizzo, Donald P.
    Univ Calif, CA 92093 USA.
    Geschwind, Michael D.
    Univ Calif San Francisco, CA USA.
    Sanchez, Henry
    Univ Calif San Francisco, CA USA.
    Appleby, Brian S.
    Case w Reserve Univ, OH USA.
    Cohen, Mark L.
    Case w Reserve Univ, OH USA.
    Safar, Jiri G.
    Case w Reserve Univ, OH USA.
    Edland, Steven D.
    Univ Calif, CA USA.
    Glatzel, Markus
    Univ Med Ctr Hamburg, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Esko, Jeffrey D.
    Univ Calif, CA USA.
    Sigurdson, Christina J.
    Univ Calif, CA USA.
    Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions2020In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 139, no 3, p. 527-546Article in journal (Refereed)
    Abstract [en]

    Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1(+/-)) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.

  • 43.
    Lantz, Linda
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Synthesis and Characterization of Thiophene-based Donor-Acceptor-Donor Heptameric Ligands for Spectral Assignment of Polymorphic Amyloid-beta Deposits2020In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 26, no 33, p. 7425-7432Article in journal (Refereed)
    Abstract [en]

    Protein deposits are associated with many devastating diseases and fluorescent ligands able to visualize these pathological entities are essential. Here, we report the synthesis of thiophene-based donor-acceptor-donor heptameric ligands that can be utilized for spectral assignment of distinct amyloid-beta (A beta) aggregates, one of the pathological hallmarks in Alzheimers disease. The ability of the ligands to selectively distinguish A beta deposits was abolished when the chemical composition of the ligands was altered. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species consisting of the same peptide or protein. In addition, such ligands might aid in interpreting the potential role of polymorphic A beta deposits in the pathogenesis of Alzheimers disease.

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  • 44.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Selegård, Robert
    Linköping University, Department of Physics, Chemistry and Biology, Biophysics and bioengineering. Linköping University, Faculty of Science & Engineering.
    Todarwal, Yogesh
    KTH Royal Inst Technol, Sweden.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Norman, Patrick
    KTH Royal Inst Technol, Sweden.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Norwegian Univ Sci & Technol, Norway.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Tyrosine Side-Chain Functionalities at Distinct Positions Determine the Chirooptical Properties and Supramolecular Structures of Pentameric Oligothiophenes2020In: ChemistryOpen, ISSN 2191-1363, Vol. 9, no 11, p. 1100-1108Article in journal (Refereed)
    Abstract [en]

    Control over the photophysical properties and molecular organization of pi-conjugated oligothiophenes is essential to their use in organic electronics. Herein we synthesized and characterized a variety of anionic pentameric oligothiophenes with different substitution patterns of L- or D-tyrosine at distinct positions along the thiophene backbone. Spectroscopic, microscopic, and theoretical studies of L- or D-tyrosine substituted pentameric oligothiophene conjugates revealed the formation of optically active pi-stacked self-assembled aggregates under acid conditions. The distinct photophysical characteristics, as well as the supramolecular structures of the assemblies, were highly influenced by the positioning of the L- or D-tyrosine moieties along the thiophene backbone. Overall, the obtained results clearly demonstrate how fundamental changes in the position of the enantiomeric side-chain functionalities greatly affect the optical properties as well as the architecture of the self-assembled supramolecular structures.

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  • 45.
    Jonson, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Carlback, Marcus
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Michno, Wojciech
    Univ Gothenburg, Sweden.
    Hanrieder, Jorg
    Univ Gothenburg, Sweden; UCL, England.
    Starkenberg, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Peter, K.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Amyloid fibril polymorphism and cell-specific toxicity in vivo2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, no sup1, p. 136-137Article in journal (Refereed)
    Abstract [en]

    Over the past several years, the toxic mechanism of proliferating misfolded proteins (MPs) as initiators and drivers of neurodegeneration has gained momentum. Nonetheless, the notion of selective vulnerability of specific cell types in neurodegenerative diseases (NDs) is largely uncharted territory. NDs show vast variations in disease onset and clinical phenotype depending on culprit MP and cell type involved. Many researchers in the field aim to target MP spreading to mitigate neurodegeneration. But there are outstanding questions:

    How can NDs stay dormant for decades before presenting clinical symptoms?How can certain patients carry large loads of MPs without showing symptoms? 

    Amyloid fibrils and oligomers are structurally heterogeneous showing conformational and ultrastructural polymorphism. This poses a challenge both for diagnostics and for therapeutic interventions. This polymorphism likely contributes to variable disease progression because protein structure determines function. Furthermore, various cell types show different sensitivity towards distinct MPs and fibril polymorphs. Unravelling how CNS support cells, glia, versus neurons handle MPs, especially Aβ amyloid linked to Alzheimer’s disease has been hampered by the fact that transgenic (tg) mice (overproducing human Aβ) show very little neurodegeneration. The situation is dramatically different in tg-Drosophila. Here, Aβ1–42 is a potent neurotoxin and is therefore arguably a more suitable model animal for such studies [1]. We addressed the question if cell toxicity is cell type and amyloid polymorph dependent.

  • 46.
    Loffler, Susanne
    et al.
    Karolinska Inst, Sweden.
    Antypas, Hails
    Karolinska Inst, Sweden.
    Choong, Ferdinand X.
    Karolinska Inst, Sweden.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Richter-Dahlfors, Agneta
    Karolinska Inst, Sweden.
    Conjugated Oligo- and Polymers for Bacterial Sensing2019In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 7, article id 265Article, review/survey (Refereed)
    Abstract [en]

    Fast and accurate detection of bacteria and differentiation between pathogenic and commensal colonization are important keys in preventing the emergence and spread of bacterial resistance toward antibiotics. As bacteria undergo major lifestyle changes during colonization, bacterial sensing needs to be achieved on different levels. In this review, we describe how conjugated oligo- and polymers are used to detect bacterial colonization. We summarize how oligothiophene derivatives have been tailor-made for detection of biopolymers produced by a wide range of bacteria upon entering the biofilm lifestyle. We further describe how these findings are translated into diagnostic approaches for biofilm-related infections. Collectively, this provides an overview on how synthetic biorecognition elements can be used to produce fast and easy diagnostic tools and new methods for infection control.

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  • 47.
    Golob-Schwarzi, Nicole
    et al.
    Med Univ Graz, Austria; Ctr Biomaker Res Med, Austria.
    Bettermann, Kira
    Med Univ Graz, Austria.
    Mehta, Anita Kuldeep
    Med Univ Graz, Austria; Dana Farber Canc Inst, MA 02215 USA.
    Kessler, Sonja M.
    Med Univ Graz, Austria; Saarland Univ, Germany.
    Unterluggauer, Julia
    Med Univ Graz, Austria.
    Krassnig, Stefanie
    Med Univ Graz, Austria.
    Kojima, Kensuke
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Chen, Xintong
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Hoshida, Yujin
    Univ Texas Southwestern Med Ctr Dallas, TX 75390 USA.
    Bardeesy, Nabeel M.
    Harvard Med Sch, MA USA.
    Mueller, Heimo
    Med Univ Graz, Austria.
    Svendova, Vendula
    Med Univ Graz, Austria.
    Schimek, Michael G.
    Med Univ Graz, Austria.
    Diwoky, Clemens
    Graz Univ Technol, Austria; Karl Franzens Univ Graz, Austria.
    Lipfert, Alexandra
    Graz Univ Technol, Austria.
    Mahajan, Vineet
    Med Univ Graz, Austria.
    Stumptner, Cornelia
    Med Univ Graz, Austria.
    Thueringer, Andrea
    Med Univ Graz, Austria.
    Froehlich, Leopold F.
    Med Univ Graz, Austria; Univ Munster, Germany.
    Stojakovic, Tatjana
    Med Univ Graz, Austria.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Kolbe, Thomas
    Univ Vet Med Vienna, Austria; Univ Bodenkultur Wien, Austria.
    Ruelicke, Thomas
    Univ Vet Med Vienna, Austria.
    Magin, Thomas M.
    Univ Leipzig, Germany.
    Strnad, Pavel
    Univ Hosp RWTH Aachen, Germany.
    Kiemer, Alexandra K.
    Ctr Biomaker Res Med, Austria.
    Moriggl, Richard
    Univ Vet Med Vienna, Austria; Ludwig Bolzmann Inst Canc Res, Austria; Med Univ Vienna, Austria.
    Haybaeck, Johannes
    Med Univ Graz, Austria; Otto von Guericke Univ, Germany.
    High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype2019In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 12, no 2, p. 256-268Article in journal (Refereed)
    Abstract [en]

    BACKGROUND amp; AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termedMallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: Weanalyzed livers of aged Krt18(-/-) mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18(-/-) mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18(-/-) mice with 26 human hepatoma cell lines and with data sets of amp;gt;300 patients with HCC, where Krt18(-/-) gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC.

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  • 48.
    Calvo-Rodriguez, Maria
    et al.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Hou, Steven S.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Snyder, Austin C.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Dujardin, Simon
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bacskai, Brian J.
    Massachusetts Gen Hosp, MA 02129 USA; Harvard Med Sch, MA 02129 USA.
    In vivo detection of tau fibrils and amyloid beta aggregates with luminescent conjugated oligothiophenes and multiphoton microscopy2019In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 7, no 1, article id 171Article in journal (Refereed)
    Abstract [en]

    The detection of amyloid beta deposits and neurofibrillary tangles, both hallmarks of Alzheimers disease (AD), is key to understanding the mechanisms underlying these pathologies. Luminescent conjugated oligothiophenes (LCOs) enable fluorescence imaging of these protein aggregates. Using LCOs and multiphoton microscopy, individual tangles and amyloid beta deposits were labeled in vivo and imaged longitudinally in a mouse model of tauopathy and cerebral amyloidosis, respectively. Importantly, LCO HS-84, whose emission falls in the green region of the spectrum, allowed for the first time longitudinal imaging of tangle dynamics following a single intravenous injection. In addition, LCO HS-169, whose emission falls in the red region of the spectrum, successfully labeled amyloid beta deposits, allowing multiplexing with other reporters whose emission falls in the green region of the spectrum. In conclusion, this method can provide a new approach for longitudinal in vivo imaging using multiphoton microscopy of AD pathologies as well as other neurodegenerative diseases associated with protein aggregation in mouse models.

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  • 49.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. MRC Lab Mol Biol, England.
    Ghetti, Bernardino
    Indiana Univ Sch Med, IN 46202 USA.
    Holton, Janice L.
    UCL Queen Sq Inst Neurol, England.
    Ling, Helen
    UCL Queen Sq Inst Neurol, England.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Goedert, Michel
    MRC Lab Mol Biol, England.
    Luminescent conjugated oligothiophenes distinguish between alpha-synuclein assemblies of Parkinsons disease and multiple system atrophy2019In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 7, no 1, article id 193Article in journal (Refereed)
    Abstract [en]

    Synucleinopathies [Parkinsons disease with or without dementia, dementia with Lewy bodies and multiple system atrophy] are neurodegenerative diseases that are defined by the presence of filamentous alpha-synuclein inclusions. We investigated the ability of luminescent conjugated oligothiophenes to stain the inclusions of Parkinsons disease and multiple system atrophy. They stained the Lewy pathology of Parkinsons disease and the glial cytoplasmic inclusions of multiple system atrophy. Spectral analysis of HS-68-stained inclusions showed a red shift in multiple system atrophy, but the difference with Parkinsons disease was not significant. However, when inclusions were double-labelled for HS-68 and an antibody specific for alpha-synuclein phosphorylated at S129, they could be distinguished based on colour shifts with blue designated for Parkinsons disease and red for multiple system atrophy. The inclusions of Parkinsons disease and multiple system atrophy could also be distinguished using fluorescence lifetime imaging. These findings are consistent with the presence of distinct conformers of assembled a-synuclein in Parkinsons disease and multiple system atrophy.

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