[Abstract Title]. - Society for Neuroscience

Poster
244. Abeta Toxicity I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 244.19/M12
Topic: C.01.c. Abeta toxicity
Support: Cure Alzheimer's Fund
Extendicare Foundation
NIH
Title: Dimeric cross-linked abeta species (CAPS) disrupt and oxidize membranes
Authors: *S. J. SOSCIA 1,2 , S. M. TUCKER 1 , R. E. TANZI 1 , R. D. MOIR 1 ;
1 Genet. and Aging Res., Massachusetts Gen. Hosp., Charlestown, MA; 2 Anat. and Neurobio.,
Boston Univ. Sch. of Med., Boston, MA
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, crosslinked
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 purify 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 peptide‟s access to metals. Membrane
disruption was highest 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.
Disclosures: S.J. Soscia , None; S.M. Tucker, None; R.E. Tanzi, None; R.D. Moir, None.