Abstract
A key event in the pathogenesis of Alzheimer's disease (AD) is the conversion of the peptide beta-amyloid (Abeta) from its soluble monomeric form into various aggregated morphologies in the brain. Apolipoprotein E (apoE) is known to act as a pathological chaperone of Abeta in this process, promoting its fibril formation from soluble Abeta by binding interaction between carboxy-terminal domain of apoE and residues 12-28 of full-length Abeta. Therefore, blocking apoE/Abeta interaction is being actively pursued as a primary therapeutic strategy for AD. Abeta20-29, a short peptide, contains the residues to competitively bind to apoE and may potentially block the interaction between apoE and full-length Abeta. However, little is known whether Abeta20-29 could block apoE/Abeta interaction to play an effective role in reducing full-length Abeta fibrillization and cytotoxicity. Utilizing fluorescence spectroscopic analysis with thioflavin T and electron microscopic study, we show here that Abeta20-29 alone was non-fibrillogenic, and had no direct effects on Abeta1-42 or Abeta1-40 aggregation. Moreover, apoE can directly promote both Abeta1-42 and Abeta1-40 aggregation and fibril formation, while this promoting effect was inhibited when adding Abeta20-29, with a dose-dependent manner. In the series of cell culture experiments, Abeta20-29 alone shows no cytotoxicity to PC12 cells as demonstrated by MTT assay, while co-incubation apoE isoforms and Abeta1-42 or Abeta1-40 shows stronger cytotoxicity as compared to Abeta1-42 or Abeta1-40 alone. When incubated with Abeta20-29, whereas such strong cytotoxic effect was concentration-dependently reduced. Taken together, we demonstrate for the first time that Abeta20-29 has no direct effect on full-length Abeta aggregation, and may competitively block the binding of full-length Abeta to apoE, resulting in an inhibitory effect on apoE's promoting full-length Abeta fibrillogenesis and Abeta-induced cytotoxicity. Our results raise the possibility that Abeta20-29 peptide blocking the interaction between full-length Abeta and apoE isoforms may be effective as a therapeutic agent for AD.
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