Year: 2008
Type: article
Abstract: Accumulation of the beta-amyloid protein (Abeta) as beta-amyloid deposits is a pathological hallmark of Alzheimer's disease (AD). Until recently the prevailing view held that insoluble fibrillar deposits of Abeta in brain were the cause of the massive neuronal death associated with the disease. However, evidence is mounting that soluble, oligomeric, cross-linked beta-amyloid protein species (CAPS), particularly dimeric forms, are highly neurotoxic and may, in fact, be the principal pathological agent in AD. Recent studies have shown that Abeta permeabilizes lipid bilayers and can disrupt other cellular membrane functions. In this study we report on the interactions of CAPS with lipid bilayers and conditions that modulate Abeta-mediated membrane disruption. We have developed novel methods to generate, fractionate, and purfy dimeric and trimeric CAPS from Abeta isoforms containing 40 (Abeta40) or 42 (Abeta42) residues. Experiments compared monomeric Abeta and purified dimeric CAPS for membrane permiabilization and peroxidation. Initial experiments identified a novel CAPS heterodimer containing both Abeta40 and Abeta42 subunits. The Abeta heterodimer has potentiated redox activity. Our data suggest membrane permeabilization by CAPS is strongly modulated by the composition of the lipid bilayer and the peptides access to metals. Membrane disruption was most pronounced for CAPS/copper complexes against mitochondrial-like membranes. In addition, CAPS also appear to induce membrane peroxidation with a rank order of CAPS40 > CAPS42 > CAPS40/42. Our preliminary data suggest the association of dimeric CAPS with membranes may play an important role in AD pathology.
Source: Alzheimer s & Dementia
Authors: Robert D. Moir, Stephanie J. Soscia, Stephanie Tucker, Rudolph E. Tanzi
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2165735042