Cause and consequence of Aβ – Lipid interactions in Alzheimer disease pathogenesis

Abstract

Self-templating propagation of protein aggregate conformations is increasingly becoming a significant factor in many neurological diseases. In Alzheimer disease (AD), intrinsically disordered amyloid-β (Aβ) peptides undergo aggregation that is sensitive to environmental conditions. High-molecular weight aggregates of Aβ that form insoluble fibrils are deposited as senile plaques in AD brains. However, low-molecular weight aggregates called soluble oligomers are known to be the primary toxic agents responsible for neuronal dysfunction. The aggregation process is highly stochastic involving both homotypic (Aβ-Aβ) and heterotypic (Aβ with interacting partners) interactions. Two of the important members of interacting partners are membrane lipids and surfactants, to which Aβ shows a perpetual association. Aβ-membrane interactions have been widely investigated for more than two decades, and this research has provided a wealth of information. Although this has greatly enriched our understanding, the objective of this review is to consolidate the information from the literature that collectively showcases the unique phenomenon of lipid-mediated Aβ oligomer generation, which has largely remained inconspicuous. This is especially important because Aβ aggregate "strains" are increasingly becoming relevant in light of the correlations between the structure of aggregates and AD phenotypes. Here, we will focus on aspects of Aβ-lipid interactions specifically from the context of how lipid modulation generates a wide variety of biophysically and biochemically distinct oligomer sub-types. This, we believe, will refocus our thinking on the influence of lipids and open new approaches in delineating the mechanisms of AD pathogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

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Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage

“…In this work we investigated whether the resistance to amyloid beta aggregation in the naked mole-rat can be traced back to specific properties of the lipid membranes of this animal, given that it is well established that lipid membranes can affect the aggregation of amyloid beta [10][11][12]13 . For example, there is a strong link between cholesterol and Alzheimer's disease, which could be related to the interaction between amyloid beta with lipid membranes [14][15][16] .…”

Unravelling the role of amino acid sequence order in the assembly and function of the amyloid-β core

“…It has been shown that the effects of lipids on amyloid aggregation are diverse, among which modulating of aggregation pathways is the most significant. 19 The charged membranes act as two-dimensional aggregation-templates to initiate the soluble random coil monomeric peptides to aggregate into β-sheet oligomers at a faster rate for native peptide. However, ThT kinetics suggests that the fibril elongation from the oligomeric state is inhibited in the presence of lipid bilayers.…”