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The influence of lysozyme and oligothiophenes on amyloid-β toxicity in models of Alzheimer’s disease
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia worldwide. Apart from dominantly inherited mutations, age is the major risk factor and as life expectancy increases the prevalence for AD escalates dramatically. AD causes substantial problems for the affected persons and their families, and the society suffers economically. To date the available treatments only temporarily relieve the symptoms, wherefore the development of a cure is of utmost importance. The etiology of AD is still inconclusive but many believe that small aggregates (oligomers) of the protein amyloid-β (Aβ) are central for the onset of AD.

The aims of this thesis were to investigate how different molecules affect the aggregation and toxicity of Aβ. In paper I and II, two oligothiophenes were studied; p-FTAA and h-FTAA and in paper III and IV the inflammatory protein lysozyme was explored. Differentiated neuroblastoma cells and Drosophila melanogaster were used as models of AD to address the issue.

The results show that p-FTAA rescues neuroblastoma cells from Aβ toxicity when Aβ is coaggregated with lysozyme. Various biophysical studies show that the co-aggregation increases the formation of fibrillar Aβ structures rich in β-sheets. Noteworthy, these Aβ fibrils were more resistant to both degradation and denaturation, and less prone to propagate seeding from Aβ monomers. Furthermore, h-FTAA, but not p-FTAA, was able to protect neuroblastoma cell toxicity when exposed to Aβ with the Arctic mutation (AβArc), which probably reflects the weaker binding of AβArc to p-FTAA, compared to h-FTAA.

Lysozyme levels were increased in CSF from patients that were both biochemically and clinically diagnosed with AD. In mice models of AD it was revealed that the mRNA increase in lysozyme correlates to increased Aβ pathology, but not to tau pathology, indicating that Aβ could drive the expression of lysozyme. To evaluate the effect for increased expression of lysozyme, co-expression of lysozyme was achieved in flies that expressed Aβ in the retina of the eyes, or in flies that expressed AβArc in the central nervous system. In all AD fly models, co-expression of lysozyme protected the cells from the Aβ induced toxicity. Of note, flies that expressed the toxic AβArc in the CNS of the flies showed an improvement in both lifespan and activity. Finally, we demonstrate that Aβ aggregating in the presence of lysozyme inhibits the cellular uptake of Aβ and also the cytotoxic effect of Aβ.

The work included in this thesis demonstrates that the oligothiophenes p-FTAA and h-FTAA, and also lysozyme have the potential to be used as treatment strategies for sporadic AD, but remarkable, also in familial AD with the highly toxic Arctic mutation. The protective mechanism of p-FTAA seems to be attributed to the ability to generate stable Aβ fibrils with reduced seeding capacity, and that lysozyme inhibits the neuronal uptake of Aβ, which could prevent both the intracellular toxicity and cell-to-cell transmission of Aβ.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 102 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1532
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology Cell Biology Immunology
Identifiers
URN: urn:nbn:se:liu:diva-131797DOI: 10.3384/diss.diva-131797ISBN: 9789176857052 (print)OAI: oai:DiVA.org:liu-131797DiVA: diva2:1033486
Public defence
2016-11-10, Berzeliussalen, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Note

Funded by: Stiftelsen för Gamla Tjänarinnor, Uppsala BIO, Alzheimerfonden, Demensfonden och Åhlén-stiftelsen.

Available from: 2016-10-07 Created: 2016-10-07 Last updated: 2016-10-07Bibliographically approved
List of papers
1. The Luminescent Oligothiophene p-FTAA Converts Toxic A beta(1-42) Species into Nontoxic Amyloid Fibers with Altered Properties
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, 9233-9243 p.Article 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: 2017-11-30
2. Beneficial effects of increased lysozyme levels in Alzheimer’s disease modelled in Drosophila melanogaster
Open this publication in new window or tab >>Beneficial effects of increased lysozyme levels in Alzheimer’s disease modelled in Drosophila melanogaster
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2016 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 283, no 19, 3508-3522 p.Article in journal (Refereed) Published
Abstract [en]

Genetic polymorphisms of immune genes that associate with higher risk to develop Alzheimer’s disease (AD) have led to an increased research interest on the involvement of the immune system in AD pathogenesis. A link between amyloid pathology and immune gene expression was suggested in a genome-wide gene expression study of transgenic amyloid mouse models. In this study, the gene expression of lysozyme, a major player in the innate immune system, was found to be increased in a comparable pattern as the amyloid pathology developed in transgenic mouse models of AD. A similar pattern was seen at protein levels of lysozyme in human AD brain and CSF, but this lysozyme pattern was not seen in a tau transgenic mouse model. Lysozyme was demonstrated to be beneficial for different Drosophila melanogaster models of AD. In flies that expressed Aβ1-42 or AβPP together with BACE1 in the eyes, the rough eye phenotype indicative of toxicity was completely rescued by coexpression of lysozyme. In Drosophila flies bearing the Aβ1-42 variant with the Arctic gene mutation, lysozyme increased the fly survival and decreased locomotor dysfunction dose dependently. An interaction between lysozyme and Aβ1-42 in the Drosophila eye was discovered. We propose that the increased levels of lysozyme, seen in mouse models of AD and in human AD cases, were triggered by Aβ1-42 and caused a beneficial effect by binding of lysozyme to toxic species of Aβ1-42, which prevented these from exerting their toxic effects. These results emphasize the possibility of lysozyme as biomarker and therapeutic target for AD.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keyword
Alzheimer’s disease, amyloid-β, Drosophila, lysozyme
National Category
Genetics Medical Genetics Developmental Biology Bioinformatics and Systems Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-131796 (URN)10.1111/febs.13830 (DOI)000386033700001 ()27562772 (PubMedID)
Available from: 2016-10-07 Created: 2016-10-07 Last updated: 2017-11-30Bibliographically approved

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