Reduced Lipid Bilayer Thickness Regulates the Aggregation and Cytotoxicity of Amyloid-β.
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.
From the Department of Chemistry.|Program in Biophysics, and.
Kyle J
KJ
Korshavn
the Department of Chemical Sciences, University of Catania, Catania 95124, Italy.
Cristina
C
Satriano
the Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
Yuxi
Y
Lin
Program in Biophysics, and.
Rongchun
R
Zhang
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109.
Mark
M
Dulchavsky
the Department of Biophysics, Bose Institute, Kolkata 700009, India, and.
Anirban
A
Bhunia
Program in Biophysics, and.|Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109.
Magdalena I
MI
Ivanova
the Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
Young-Ho
YH
Lee
the Department of Chemical Sciences, University of Catania, Catania 95124, Italy.
Carmelo
C
La Rosa
the Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Korea.
Mi Hee
MH
Lim
From the Department of Chemistry, ramamoor@umich.edu.|Program in Biophysics, and.
Ayyalusamy
A
Ramamoorthy
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D066329:Protein Aggregates; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D066329:Protein Aggregates; C015153:1,2-dilauroylphosphatidylcholine; C017251:1,2-oleoylphosphatidylcholine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
Alzheimer disease; amyloid-beta (AB); lipid bilayer; protein misfolding; toxicity