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  • 1. Bestill onlineKjøp publikasjonen >>
    Sandberg, Alexander
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Polymorphic protein aggregation in tauopathies2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Alzheimer’s disease(s) comprises one of the most common and costly neurodegenerative diseases. With a larger population and an increasing life expectancy, amyloid diseases (with age as one of the most prominent risk factors) will generate an even larger burden on healthcare. We know that protein misfolding is involved in the disease process but lack a complete understanding of the mechanism behind these diseases, both the sporadic and hereditary variants. It is not always known whether it is a gain-of-toxic function or loss‐of‐function that causes the neurodegeneration. To determine the correct diagnosis is a major challenge. If diagnosed, only a few amyloid diseases can be treated today.

    Amyloids are highly ordered filamentous protein aggregates with a β‐sheet structure. From identical or similar amino acid sequences, a large variety of structures can be formed by different secondary and tertiary structures and by different packing of the individual filaments. This is known as fibril polymorphism.

    This work focuses on characterization on two proteins involved in Alzheimer’s disease and other neurodegenerative diseases, namely Amyloid‐β (Aβ) and microtubule associated protein tau (tau). In order to investigate the properties of these proteins in vitro it is important to have protocols for production of recombinant protein that enables characterization of these aggregation prone proteins. We present protocols for recombinant expression, purification and non‐denaturing fibrillation assays used in our lab to produce and analyze Aβ, tau and the prion protein.

    Development of new ligands for characterization of fibrils is an important way of investigating different fibrillary structures and characterizing and distinguishing between the different polymorphs of aggregates. We showed that the central benzene ring of the amyloid ligand X‐34 can be exchanged for other heterocyclic motifs and still retain targeting of the “Congo red” binding site. The compounds do not compete with the Pittsburgh compound B (PiB) binding site on recombinant Aβ fibrils.

    We also characterized tau fibrils formed from seeding with tau aggregates from patients diagnosed with different neurodegenerative tauopathies. We use aggregation kinetics to test the seeding activity on two different sequence isoforms of tau, 0N3R and 0N4R. Fibrillation kinetics, an array of recently developed ligands (including the X‐34 analogs) and electron microscopy were used to characterize different polymorphs of the tau aggregates formed by seeded templating from patient derived seeds. Our data showed that brains contain seeds with different morphologies even with in patients diagnosed with the same disease.

    Investigations of the rare tau mutant G273R found in a patient with a presumed tauopathy also highlights the problem with proper diagnostics. Our results reveal that in vitro this mutation change the binding properties of 0N4R tau to the cytoskeletal proteins microtubule and F‐actin. Furthermore, we could show that when seeded, the fibril formation seeding activity followed a sequence similarity dependent manner. In fibrils formed during heparin-induced aggregation we can be distinguished between wild type and mutant tau as they form fibrils with different thickness. Our in vitro biophysical data support that the G237R mutant is causing a 4R tauopathy.

    The work in this thesis increase our knowledge in the field of tau aggregation and tau fibril polymorphism.

    Delarbeid
    1. Purification and Fibrillation of Recombinant Human Amyloid-ß, Prion Protein, and Tau Under Native Conditions
    Åpne denne publikasjonen i ny fane eller vindu >>Purification and Fibrillation of Recombinant Human Amyloid-ß, Prion Protein, and Tau Under Native Conditions
    2018 (engelsk)Inngår i: Amyloid Proteins: Methods and Protocols / [ed] Einar M. Sigurdsson, Miguel Calero and María Gasset, Humana Press, 2018, Vol. 1779, s. 147-166Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Protein misfolding, aggregation, and amyloid formation is involved in a large number of diseases. Recombinantly expressed proteins to study the amyloid fibril formation process are important for mechanistic studies. We here report protocols for production, purification, and fibrillation of three different proteins commonly found in cerebral amyloid; Aß and Tau found in Alzheimers disease, Chronic traumatic brain injury, Corticobasal degeneration, and Progressive Supranuclear Palsy and human prion protein found in Creutzfeldt-Jakobs disease. The three protocols have in common that the protein is in a pH-neutral phosphate saline buffer during fibrillation to mimic their endogenous near physiological environment.

    sted, utgiver, år, opplag, sider
    Humana Press, 2018
    Serie
    Methods in Molecular Biology, E-ISSN 1940-6029 ; 1779
    Emneord
    Amyloid; Aß; Fibrillation; Neurodegenerative disease; Prion protein; Purification; Recombinant; Tau
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-152517 (URN)10.1007/978-1-4939-7816-8_10 (DOI)29886532 (PubMedID)9781493978151 (ISBN)9781493978168 (ISBN)
    Tilgjengelig fra: 2019-03-28 Laget: 2019-03-28 Sist oppdatert: 2019-11-08
    2. Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues
    Åpne denne publikasjonen i ny fane eller vindu >>Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues
    Vise andre…
    2018 (engelsk)Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, nr 28, s. 7210-7216Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We revisited the Congo red analogue 2,5-bis(4-hydroxy-3-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimers disease (AD) pathology comprising A beta and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of A beta 1-42 (13-300nmK(d)) and Tau (16-200nmK(d)) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant A beta 1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for A pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of A fibrils.

    sted, utgiver, år, opplag, sider
    WILEY-V C H VERLAG GMBH, 2018
    Emneord
    Alzheimers disease; amyloid ligands; dyes/pigments; fluorescence; microscopy
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-148653 (URN)10.1002/chem.201800501 (DOI)000434074800013 ()29543355 (PubMedID)
    Merknad

    Funding Agencies|China Scholarship Council; Swedish Research Council [2015-04521]; Goran Gustafsson Foundation; Swedish Alzheimer Foundation; Swedish Brain foundation; Linkoping University (LiU-Neuro); NIH/NINDS [R21 NS080576]

    Tilgjengelig fra: 2018-06-18 Laget: 2018-06-18 Sist oppdatert: 2019-11-08
  • 2.
    Sandberg, Alexander
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Purification and Fibrillation of Recombinant Human Amyloid-ß, Prion Protein, and Tau Under Native Conditions2018Inngår i: Amyloid Proteins: Methods and Protocols / [ed] Einar M. Sigurdsson, Miguel Calero and María Gasset, Humana Press, 2018, Vol. 1779, s. 147-166Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Protein misfolding, aggregation, and amyloid formation is involved in a large number of diseases. Recombinantly expressed proteins to study the amyloid fibril formation process are important for mechanistic studies. We here report protocols for production, purification, and fibrillation of three different proteins commonly found in cerebral amyloid; Aß and Tau found in Alzheimers disease, Chronic traumatic brain injury, Corticobasal degeneration, and Progressive Supranuclear Palsy and human prion protein found in Creutzfeldt-Jakobs disease. The three protocols have in common that the protein is in a pH-neutral phosphate saline buffer during fibrillation to mimic their endogenous near physiological environment.

  • 3.
    Zhang, Jun
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi.
    Sandberg, Alexander
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Wu, Xiongyu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Lindgren, Mikael
    Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway.
    Konradsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils2017Inngår i: ACS Omega, ISSN 2470-1343, Vol. 2, nr 8, s. 4693-4704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It was previously reported that two naphthyl-based trans-stilbene probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (1) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (3), can bind to both native transthyretin (TTR) and misfolded protofibrillar TTR at physiological concentrations, displaying distinct emission maxima bound to the different conformational states (>100 nm difference). To further explore this amyloid probe scaffold to obtain extended fluorescence lifetimes, two new analogues with expanded aromatic ring systems (anthracene and pyrene), (E)-4-(2-(anthracen-2-yl)vinyl)benzene-1,2-diol (4) and (E)-4-(2-(pyren-2-yl)vinyl)benzene-1,2-diol (5), were synthesized employing the palladium-catalyzed Mizoroki–Heck reaction. (E)-4-Styrylbenzene-1,2-diol (2), 3, 4, and 5 were investigated with respect to their photophysical properties in methanol and when bound to insulin, lysozyme, and Aβ1-42 fibrils, including time-resolved fluorescence measurements. In conclusion, 4 and 5 can bind to both native and fibrillar TTR, becoming highly fluorescent. Compounds 2–5 bind specifically to insulin, lysozyme, and Aβ1-42 fibrils with an apparent fluorescence intensity increase and moderate binding affinities. The average fluorescence lifetimes of the probes bound to Aβ1-42 fibrils are 1.3 ns (2), 1.5 ns (3), 5.7 ns (4), and 29.8 ns (5). In summary, the variable aromatic moieties of the para-positioned trans-stilbenoid vinyl-benzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene showed that the extended conjugated systems retained the amyloid targeting properties of the probes. Furthermore, both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes. These attractive probe properties should improve amyloid detection and characterization by fluorescence-based techniques.

  • 4.
    Zhang, Jun
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Wang, Jun
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Sandberg, Alexander
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Wu, Xiongyu
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Nyström, Sofie
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    LeVine, Harry III
    Sanders-Brown Center on Aging, University of Kentucky, KY 40536-0230, Lexington, USA..
    Konradsson, Peter
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Hammarström, Per
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Durbeej, Bo
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska fakulteten.
    Lindgren, Mikael
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Department of Physics, Norwegian University of Science and Technology, 7491, Trondheim, Norway..
    Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.2018Inngår i: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 19, nr 22, s. 3001-3009Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site.less thanbr /greater than (© 2018 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.)

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