Abeta20-29 peptide blocking apoE/Abeta interaction reduces full-length Abeta42/40 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 (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.
Hao
Jian
J
Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province, China.
Zhang
Wei
W
Zhang
Peng
P
Liu
Rui
R
Liu
Linna
L
Lei
Gesheng
G
Su
Changjun
C
Miao
Jianting
J
Li
Zhuyi
Z
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors*; D052160:Benzothiazoles; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005456:Fluorescent Dyes; D006801:Humans; D008854:Microscopy, Electron; D009454:Neurofibrils / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D013778:Tetrazolium Salts; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; C509685:amyloid beta-protein (20-29); C009462:thioflavin T; C022616:thiazolyl blue