Reduced Lipid Bilayer Thickness Regulates the Aggregation and Cytotoxicity of Amyloid-β

Abstract

Edited by Paul E. FraserThe aggregation of amyloid-␤ (A␤) on lipid bilayers has been implicated as a mechanism by which A␤ 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 A␤ misfolding is unclear. Here, we studied peptide-lipid interactions in synthetic bilayers of the shortchain lipid dilauroyl phosphatidylcholine (DLPC) as a simplified model for diseased bilayers to determine their impact on A␤ aggregate, protofibril, and fibril formation. A␤ 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 A␤ 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 A␤ aggregation on neuronal bilayers, and pathological lipid oxidation may contribute to A␤ misfolding.

N‐Terminal Charged Residues of Amyloid‐β Peptide Modulate Amyloidogenesis and Interaction with Lipid Membrane

“…In addition, interactions of lipid membrane and amyloidogenic proteins are significantly influenced by the properties of lipids, such as the type of lipids, hydrophobicity, and length of acyl chain. [18] Our results suggest that the amine moiety in the head group of POPC, instead of the phosphate group, is more responsible for early interacting with Aβ peptide, reinforcing the importance of chemical properties of lipids in affecting interactions of membrane and amyloidogenic proteins. [19] …”

Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study

“…The above may indicate that, unlike Aβ 1–40, which is commonly formed in the brain (Yin et al, 2007), Aβ 1–42 shows a change in its spatial conformation, promoted by oxidative stress (Butterfield et al, 2013; Korshavn et al, 2017). Aβ 1–42 is an oxidized peptide that changes its spatial conformation from β-turn to β-sheet as proven by this work.…”

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

“…One recurring question has been how membrane interactions can modulate the Aβ misfolding and aggregation process [50–52]. Others have used ssNMR to examine the conformation of pre-fibrillar Aβ oligomers and protofibrils, and compare them to those of the mature fibrils [53–60].…”