Modulation of Alzheimer's Aβ protofilament-membrane interactions by lipid headgroups.

Abstract:

:The molecular pathogenesis of Alzheimer's disease (AD) is complex and sparsely understood. The relationship between AD's amyloid β (Aβ) peptides and neuronal membranes is central to Aβ's cytotoxicity and is directly modulated by the composition of the lipid headgroups. Molecular studies of the insertion of model Aβ40 protofilaments in lipid bilayers revealed strong interactions that affect the structural integrity of both the membranes and the ordered amyloid aggregates. In particular, electrostatics plays a crucial role in the interaction between Aβ protofilaments and palmytoil-oleoyl-phosphatidylethanolamine (POPE) lipids, a common component of neuronal plasma membranes. Here, we use all-atom molecular dynamics and steered molecular dynamics simulations to systematically compare the effects that POPE and palmytoil-oleoyl-phosphatidylcholine (POPC) headgroups have on the Aβ-lipid interactions. We find that Aβ protofilaments exhibit weaker electrostatic interactions with POPC headgroups and establish significantly shorter-lived contacts with the POPC bilayer. This illustrates the crucial yet complex role of electrostatic and hydrogen bonding interactions in modulating the anchoring and insertion of Aβ peptides into lipid bilayers. Our study reveals the atomistic details behind the barrier created by the lipid headgroup region in impeding solution-aggregated fibrillar oligomers to spontaneously insert into POPC bilayers, in contrast to the POPE case. While the biological reality is notoriously more complex (e.g., including other factors such as cholesterol), our results evidence a simple experimentally and computationally testable case for probing the factors that control the insertion of Aβ oligomeric aggregates in neuronal cell membranes--a process central to their neurotoxicity.

journal_name

ACS Chem Neurosci

authors

Tofoleanu F,Brooks BR,Buchete NV

doi

10.1021/cn500277f

subject

Has Abstract

pub_date

2015-03-18 00:00:00

pages

446-55

issue

3

issn

1948-7193

journal_volume

6

pub_type

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