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AuthorClaus, Stephaniedc.contributor.author
Date of accession2018-07-04T13:08:48Zdc.date.accessioned
Available in OPARU since2018-07-04T13:08:48Zdc.date.available
Year of creation2017dc.date.created
Date of first publication2018-07-04dc.date.issued
AbstractThe formation of amyloid fibrils inside the body underlies a range of diseases, including systemic AA amyloidosis and Alzheimer’s disease. In the case of AA amyloidosis, the acute-phase serum amyloid A (SAA1) protein is dramatically increased, truncated by proteases and deposited as amyloid fibrils in the extracellular space of spleen, liver and kidneys. Alzheimer’s disease, on the other hand, is the most common cause of dementia and characterized by the deposition of amyloid beta (Aβ) protein in the brain. Both diseases are known to involve macrophages or phagocytic active cells in the formation of amyloid fibrils. However, the cellular mechanisms of fibril formation of AA amyloidosis and Alzheimer’s disease have not yet been fully understood. By using a murine AA amyloidosis cell culture model and a human Alzheimer’s disease cell culture model, we investigate both disorders on a cellular level. We show that murine macrophage-like J774A.1 cells as well as human differentiated THP-1 cells form extracellular CR green birefringent amyloid deposits upon exposure to murine SAA1 protein and human Aβ(1-40) protein, respectively. Further, during amyloid formation, SAA1 protein is internalized by the cells via clathrin-dependent endocytosis and trafficked to the lysosomes. Using a Förster resonance energy transfer sensor, we observe that the SAA1 protein starts to aggregate intracellularly. For both disorders, we find that intracellular aggregation disturbs the integrity of vesicular membranes, leading to lysosomal leakage and, consequently, resulting in cellular death. Apoptotic death of the cells causes the release of intracellular aggregates to the extracellular space, where they can be detected as CR green birefringent amyloid deposits. Subsequently, these extracellular deposits are able to seed fibrillation of extracellular SAA1 protein. Using scanning electron microscopy, we find three main types of fibril network structures, denoted amorphous meshwork, fibril bundle and amyloid star, in Aβ amyloid deposits. In both disorders, we show that amyloid fibrils interact with surrounding cells. In AA amyloidosis, we observe progressive clustering of the cells, often enclosing large-sized amyloid deposits and dead cells. In Alzheimer’s disease, however, we find fibril bundles extended into tubular invaginations of the plasma membrane of surrounding cells and lipid assemblies of different sizes. Additionally, in AA amyloidosis we show that non-fibrillar and fibrillar SAA1 protein can be transferred between cultured J774A.1 cells, with the exchange occurring faster with the smaller, non-fibrillar SAA1 protein than with the fibrillar SAA1. Experiments in which physical interactions of cells are prevented by using a semipermeable membrane show a significant reduction in the exchange efficiency of non-fibrillar and fibrillar SAA1 protein. Using scanning electron microscopy, we observe physical interactions between cultured cells, which leads to the conclusion that the transfer of non-fibrillar and fibrillar SAA1 protein depends on direct cell-to-cell interactions. Considering the worldwide distribution, high incidence and progressive prevalence of Alzheimer’s disease as well as the occurrence of systemic AA amyloidosis in several mammals and its possible transmission through nourishment, the understanding of the processes underlying Alzheimer’s disease and AA amyloidosis is highly relevant. To achieve this, an understanding of the molecular mechanisms of amyloid formation and cell-to-cell transmission of amyloid proteins is crucial and can potentially support the research of other protein misfolding diseases.dc.description.abstract
Languageendc.language.iso
PublisherUniversität Ulmdc.publisher
Articles in publ.Shen Han, Marius Kollmer, Daniel Markx, Stephanie Claus, Paul Walther and Marcus Fändrich. (2017) Amyloid plaque structure and cell surface interactions of β-amyloid fibrils revealed by electron tomography. Sci Rep. 7:43577. doi: 10.1038/srep43577dc.relation.haspart
Articles in publ.Stephanie Claus, Katrin Meinhardt, Tobias Aumüller, Ioana Puscalau-Girtu, Julia Linder, Christian Haupt, Paul Walther, Tatiana Syrovets, Thomas Simmet and Marcus Fändrich. (2017) Cellular mechanism of fibril formation from serum amyloid A1 protein. EMBO Rep. pii: e201643411. doi: 10.15252/embr.201643411dc.relation.haspart
Articles in publ.Stephanie Claus, Ioana Puscalau-Girtu, Paul Walther, Tatiana Syrovets, Thomas Simmet, Christian Haupt and Marcus Fändrich. (2017) Cell-to-cell transfer of SAA1 protein in a cell culture model of systemic AA amyloidosis. Sci Rep. 7:45683. doi: 10.1038/srep45683.ädc.relation.haspart
LicenseStandarddc.rights
Link to license texthttps://oparu.uni-ulm.de/xmlui/license_v3dc.rights.uri
KeywordAA Amyloidosisdc.subject
KeywordFibril formationdc.subject
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHProteostasis deficienciesdc.subject.mesh
MeSHAlzheimer diseasedc.subject.mesh
MeSHMechanotransduction, cellulardc.subject.mesh
MeSHSerum amyloid A proteindc.subject.mesh
MeSHAmyloidosisdc.subject.mesh
TitleCellular mechanism of amyloid formation in Alzheimer’s disease and systemic AA amyloidosisdc.title
Resource typeDissertationdc.type
Date of acceptance2017-12-05dcterms.dateAccepted
RefereeFändrich, Marcusdc.contributor.referee
RefereeGronemeyer, Thomasdc.contributor.referee
RefereeGursky, Olgadc.contributor.referee
DOIhttp://dx.doi.org/10.18725/OPARU-7821dc.identifier.doi
PPN1026919606dc.identifier.ppn
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-7878-8dc.identifier.urn
GNDAmyloidosedc.subject.gnd
GNDAlzheimerkrankheitdc.subject.gnd
FacultyFakultät für Naturwissenschaftenuulm.affiliationGeneral
InstitutionInstitut für Proteinbiochemieuulm.affiliationSpecific
InstitutionInstitut für Molekulare Genetik und Zellbiologieuulm.affiliationSpecific
Grantor of degreeFakultät für Naturwissenschaftenuulm.thesisGrantor
DCMI TypeTextuulm.typeDCMI
CategoryPublikationenuulm.category
FundingCarl-Zeiss-Stiftung, Germanyuulm.funding
University Bibliographyjauulm.unibibliographie


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