Comparison of Synthetic Neuronal Model Membrane Mimics in Amyloid Aggregation at Atomic Resolution.

Alzheimer's disease (AD) is a severe neurodegenerative disorder caused by abnormal accumulation of toxic amyloid plaques of the amyloid-beta (Aβ) or the tau proteins in the brain. The plaque deposition leading to the collapse of the cellular integrity is responsible for a myriad of surface phenomena acting at the neuronal lipid interface. Recent years have witnessed dysfunction of the blood-brain barriers (BBB) associated with AD. Several studies support the idea that BBB acts as a platform for formation of misfolded Aβ peptide, promoting oligomerization and fibrillation, compromising the overall integrity of the central nervous system. While the amyloid plaque deposition has been known to be responsible for the collapse of the BBB membrane integrity, the causal effect relationship between BBB and Aβ amyloidogenesis remains unclear. In this study, we have used physiologically relevant synthetic model membrane systems to gain atomic insight into the functional aspects of the lipid interface. Here, we have used a minimalist BBB mimic, POPC/POPG/Cholesterol/GM1, to compare with the native BBB (total lipid brain extract (TLBE)), to understand the molecular events occurring in the membrane-induced Aβ40 amyloid aggregation. Our study showed that the two membrane models accelerated the Aβ40 aggregation kinetics with differential secondary structural transitions of the peptide. The observed structural transitions are defined by the lipid compositions, which in turn undermines the differences in lipid surface phenomena, leading to peptide cellular toxicity in neuronal membrane.