Aβ20-29 peptide blocking apoE/Aβ interaction reduces full-length Aβ42/40 fibril formation and cytotoxicity in vitro

A key event in the pathogenesis of Alzheimer's disease (AD) is the conversion of the peptide beta-amyloid (A beta) from its soluble monomeric form into various aggregated morphologies in the brain. Apolipoprotein E (apoE) is known to act as a pathological chaperone of A beta in this process, promoting its fibril formation from soluble A beta by binding interaction between carboxy-terminal domain of apoE and residues 12-28 of full-length All Therefore, blocking apoE/A beta interaction is being actively pursued as a primary therapeutic strategy for A beta. A beta 20-29, a short peptide, contains the residues to competitively bind to apoE and may potentially block the interaction between apoE and full-length A beta. However, little is known whether A beta 20-29 could block apoE/A beta interaction to play an effective role in reducing full-length A beta fibrillization and cytotoxicity. Utilizing fluorescence spectroscopic analysis with thioflavin T and electron microscopic study, we show here that A beta 20-29 alone was non-fibrillogenic, and had no direct effects on A beta 1-42 or A beta 1-40 aggregation. Moreover, apoE can directly promote both A beta 1-42 and A beta 1-40 aggregation and fibril formation, while this promoting effect was inhibited when adding A beta 20-29, with a dose-dependent manner. In the series of cell culture experiments, A beta 20-29 alone shows no cytotoxicity to PC12 cells as demonstrated by MTT assay, while co-incubation apoE isoforms and A beta 1-42 or A beta 1-40 shows stronger cytotoxicity as compared to A beta 1-42 or A beta 1-40 alone. When incubated with A beta 20-29, whereas such strong cytotoxic effect was concentration-dependently reduced. Taken together, we demonstrate for the first time that A beta 20-29 has no direct effect on full-length All aggregation, and may competitively block the binding of full-length A beta to apoE, resulting in an inhibitory effect on apoE's promoting full-length A beta fibrillogenesis and A beta-induced cytotoxicity. Our results raise the possibility that A beta 20-29 peptide blocking the interaction between full-length A beta and apoE isoforms may be effective as a therapeutic agent for AD. (C) 2010 Elsevier Ltd. All rights reserved.