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Sandin, Linnea
Publications (6 of 6) Show all publications
Civitelli, L., Sandin, L., Nelson, E., Iqbal Khattak, S., Brorsson, A.-C. & Kågedal, K. (2016). The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties. Journal of Biological Chemistry, 291(17), 9233-9243
Open this publication in new window or tab >>The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties
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2016 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 291, no 17, p. 9233-9243Article in journal (Refereed) Published
Abstract [en]

Aggregation of the amyloid-(beta) peptide (A beta) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the A beta peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the A beta fibrillation pathway may be a valid approach to reduce A beta cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic A beta species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting A beta-mediated cytotoxicity. Moreover, p-FTAA bound to early formed A beta species and induced a rapid formation of beta-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable A beta species that were nontoxic which indicates that p-FTAA might have therapeutic potential.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2016
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-128747 (URN)10.1074/jbc.M115.696229 (DOI)000374849000033 ()26907684 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Torsten Soderberg Foundation; Alzheimer Foundation; Dementia Foundation; Linkoping University Neurobiology Center

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2018-03-20
Helmfors, L., Boman, A., Civitelli, L., Nath, S., Sandin, L., Janefjord, C., . . . Kågedal, K. (2015). Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease. Neurobiology of Disease, 83, 122-133
Open this publication in new window or tab >>Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
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2015 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, p. 122-133Article in journal (Refereed) Published
Abstract [en]

The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Lysozyme, Biomarker, Alzheimer disease, Drosophila, Aβ aggregation
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122341 (URN)10.1016/j.nbd.2015.08.024 (DOI)000366230000012 ()26334479 (PubMedID)
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
Armstrong, A., Mattsson, N., Appelqvist, H., Janefjord, C., Sandin, L., Agholme, L., . . . Kågedal, K. (2014). Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease. Neuromolecular medicine, 16(1), 150-160
Open this publication in new window or tab >>Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
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2014 (English)In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, no 1, p. 150-160Article in journal (Refereed) Published
Abstract [en]

The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

Place, publisher, year, edition, pages
Humana Press, 2014
Keywords
PICALM; DRAM; TFEB; Cathepsins; Proteasome; hsc70
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-105235 (URN)10.1007/s12017-013-8269-3 (DOI)000331101900015 ()
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2018-01-11
Fryland, L., Forsberg, P., Sandin, L., Wilhelmsson, P., Lindblom, P., Nyman, D., . . . Ekerfelt, C. (2012). Biomarkers in blood a few days after a bite by a Borrelia burgdorferi infected tick:: Asymptomatic Borrelia burgdorferi-infected subjects show higher Th1-associated response compared with subjects who later develop Lyme borreliosis.
Open this publication in new window or tab >>Biomarkers in blood a few days after a bite by a Borrelia burgdorferi infected tick:: Asymptomatic Borrelia burgdorferi-infected subjects show higher Th1-associated response compared with subjects who later develop Lyme borreliosis
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2012 (English)Manuscript (preprint) (Other academic)
Abstract [en]

The clinical outcome following infection with Borrelia (B.) burgdorferi sensu lato (s.l.) differs between individuals, ranging from asymptomatic infection to Lyme borreliosis (LB) with persistent symptoms post-treatment. Previous studies in mice and humans have generated the hypothesis that a successful outcome of B. burgdorferi s.l. infection is associated with an early strong pro-inflammatory T helper (Th)1-like immune response. The aim of this study was to assess the early course of events in B. burgdorferi s.l.-associated inflammation by screening for possible early immune biomarkers in peripheral blood from newly tick-bitten persons. The study subjects bitten by B. burgdorferi s.l.-infected ticks were divided into (1) those later developing clinical LB, (2) those who developed anti-B. burgdorferi s.l. antibodies but not clinical LB, (3) those who neither developed antibodies nor clinical LB. A fourth group consisted of bitten study subjects without development of antibodies or clinical LB. Two sets of samples, both comprising all four groups, were collected in order to repeat the analyses and confirm the data. Sera or plasma collected a few days after the tick bite were analysed for 18 biomarkers (IL-1β, IL-6, CXCL8/IL-8, IL-12p70, IL-17A, IL-27, TNF, CCL18, CCL20, CCL22, CXCL1, CXCL9, CXCL10, CXCL11, calprotectin, MMP-3, MMP-8, MMP-9) by multiplex bead assay and ELISA. In the first set of samples, the neutrophil activation marker calprotectin was increased in subjects who developed clinical LB compared with subjects who developed antibodies against B. burgdorferi s.l. but did not develop LB. However, the finding could not be confirmed in the second set of samples, thus the study failed to identify an early prognostic marker for development of clinical LB. Interestingly, both sets of samples showed increases in two different Th1-associated markers, CXCL10 and IL-12p70, respectively, in subjects who following a bite by a B. burgdorferi s.l.-infected tick developed antibodies against B. burgdorferi s.l. but did not develop LB compared with subjects who developed clinical LB, thus supporting the hypothesis of an early strong Th1-response being important for optimal resolution of B. burgdorferi s.l. infection.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-86267 (URN)
Note

TBD Sting study group (Tick-Borne Diseases Sting study group) consists of: Clas Ahlm,Johan Berglund, Sven Bergström, Sten-Anders Carlsson, Ingvar Eliasson, Mats Haglund,Anna J Henningsson, Christian Jansson, Liselott Lindvall, Peter Nolskog, Marika Nordberg,Susanne Olausson, Katarina Ornstein, Johanna Sjöwall, Barbro Hedin Skogman, IvarTjernberg, Mari-Anne Åkeson.

Available from: 2012-12-12 Created: 2012-12-12 Last updated: 2013-08-29Bibliographically approved
Appelqvist, H., Sandin, L., Björnström, K., Saftig, P., Garner, B., Öllinger, K. & Kågedal, K. (2012). Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content. PLoS ONE, 7(11)
Open this publication in new window or tab >>Sensitivity to Lysosome-Dependent Cell Death is Directly Regulated by Lysosomal Cholesterol Content
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11Article in journal (Refereed) Published
Abstract [en]

Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1) protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2), which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determined the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

Place, publisher, year, edition, pages
Public Library of Science, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85004 (URN)10.1371/journal.pone.0050262 (DOI)000311885300096 ()23166840 (PubMedID)
Note

Funding Agencies|Swedish Research Council|2010-3463|Deutsche Forschungsgemeinschaft||foundation of Olle Engqvist||foundation of Ake Wiberg||

Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
Helmfors, L., Armstrong, A., Civitelli, L., Sandin, L., Nath, S., Janefjord, C., . . . Kågedal, K.A protective role of lysozyme in Alzheimer disease.
Open this publication in new window or tab >>A protective role of lysozyme in Alzheimer disease
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Alzheimer disease (AD) is a devastating neurodegenerative disorder where extracellular plaques composed of amyloid β (Aβ) peptides and neuroinflammation are some of the main hallmarks of the disease. Activated microglial cells, which are the resident macrophages in the central nervous system, are suggested to trigger the inflammation response in AD. To discover neuroinflammation biomarkers would be important to reveal the pathological mechanisms of AD and develop therapies that target inflammation mediators. Lysozyme is part of the innate immune system and is secreted from macrophages during various inflammation conditions. However, the involvement of lysozyme in AD pathology has not been explored previously. We have discovered that lysozyme is up-regulated in cerebrospinal fluid from AD patients. Cells exposed to Aβ increased the expression of lysozyme indicating that Aβ might be responsible for the upregulation of lysozyme detected in cerebrospinal fluid. In vitro studies revealed that lysozyme binds to monomeric Aβ1-42 and alters the aggregation pathway counteracting formation of toxic Aβ species. In a newly developed Drosophila model, co-expression of lysozyme with Aβ in brain neurons reduced the formation of insoluble Aβ species, prolonged the survival and improved the activity of the double transgenic flies compared to flies only expressing Aβ. Our findings identify lysozyme as a modulator of Aβ aggregation and toxicity and our discoveries has the potential to be used for development of new treatment strategies and to use lysozyme as a biomarker for AD.

Keywords
Lysozyme, Biomarker, Alzheimer disease, Drosophila, CSF, Aβ aggregation
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-106646 (URN)
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2014-05-16Bibliographically approved
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