Probing Structural Features of Alzheimer's β-Amyloid Ion Channels in Membranes Using Aβ Mutants

Abstract

A current hypothesis for the pathology of Alzheimer's disease (AD) proposes that amyloid-beta (Aβ) peptides induce uncontrolled, neurotoxic ion flux across cellular membranes. The resulting inability of neurons to regulate their intracellular concentration of ions, in particular calcium ions, has been associated with cell death and may thus contribute to cognitive impairment typical for AD. The mechanism of the ion flux is not fully understood since no experimentally based Aβ channel structures at atomic resolution are currently available, and few polymorphisms have been predicted by computational models. Structural models and experimental evidence suggest that Aβ channel is an assembly of loosely-associated mobile β-sheet subunits. Histidines were proven to be on or near the mouth of the Aβ pore, but no other amino acids have been tested. Using planar lipid bilayers, we present a study showing that amino acidic substitutions can be used to infer which residues line the pore and are water accessible. For example, the substitution of F19P is capable of undermining the amyloid structure such that bilayer membranes exposed to it do not support ion channel formations for prolonged periods of time. This and other structural information on or in membrane are needed to aid drug design aiming to control unregulated Aβ ion fluxes.Funded by extramural program NIH-NIA (RL), NCI Contract HHSN261200800001E (RN) and DOD, NSF and ARCS (LSC).