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Reduced lipid bilayer thickness regulates the aggregation and cytotoxicity of amyloid-β

Author(s)
Korshavn, Kyle J.Satriano, CristinaLin, YuxiZhang, RongchunDulchavsky, MarkBhunia, AnirbanIvanova, Magdalena I.Lee, Young-HoRosa, Carmelo LaLim, Mi HeeRamamoorthy, Ayyalusamy
Issued Date
2017-03
DOI
10.1074/jbc.M116.764092
URI
https://scholarworks.unist.ac.kr/handle/201301/21796
Fulltext
http://www.jbc.org/content/292/11/4638.abstract
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v.292, no.11, pp.4638 - 4650
Abstract
The aggregation of amyloid-β (Aβ) on lipid bilayers has been implicated as a mechanism by which Aβ exerts its toxicity in Alzheimer's disease (AD). Lipid bilayer thinning has been observed during both oxidative stress and protein aggregation in AD, but whether these pathological modifications of the bilayer correlate with Aβ misfolding is unclear. Here, we studied peptide-lipid interactions in synthetic bilayers of the short-chain lipid dilauroyl phosphatidylcholine (DLPC) as a simplified model for diseased bilayers to determine their impact on Aβ aggregate, protofibril, and fibril formation. Aβ aggregation and fibril formation in membranes composed of dioleoyl phosphatidylcholine (DOPC) or 1- palmitoyl-2-oleoyl phosphatidylcholine mimicking normal bilayers served as controls. Differences in aggregate formation and stability were monitored by a combination of thioflavin-T fluorescence, circular dichroism, atomic force microscopy, transmission electron microscopy, and NMR. Despite the ability of all three lipid bilayers to catalyze aggregation, DLPC accelerates aggregation at much lower concentrations and prevents the fibrillation of Aβ at low micromolar concentrations. DLPC stabilized globular, membrane-associated oligomers, which could disrupt the bilayer integrity. DLPC bilayers also remodeled preformed amyloid fibrils into a pseudo-unfolded, molten globule state, which resembled on-pathway, protofibrillar aggregates. Whereas the stabilized, membrane-associated oligomers were found to be nontoxic, the remodeled species displayed toxicity similar to that of conventionally prepared aggregates. These results provide mechanistic insights into the roles that pathologically thin bilayers may play in Aβ aggregation on neuronal bilayers, and pathological lipid oxidation may contribute to Aβ misfolding.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
ISSN
0021-9258
Keyword
ALZHEIMERS-DISEASEA-BETAALPHA-SYNUCLEINMEMBRANE FRAGMENTATIONPHOSPHOLIPID-BILAYERSPROTEIN AGGREGATIONOXIDATIVE STRESSFIBRILSBINDINGSTATE

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