Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 75, Issue 2, Pages 162-171Publisher
WILEY
DOI: 10.1002/jnr.10859
Keywords
Alzheimer's disease (AD); beta-amyloid (AP); beta-amyloid 25-35 (A beta 25-35); thioflavin T (ThT); Atomic Force Microscope (AFM); cytotoxicity
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Funding
- NIA NIH HHS [AG17984] Funding Source: Medline
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We examined the effects of co-incubating nine different Abeta peptide fragments with full-length Abeta1-40 (Abeta40) on protein aggregation. Six fragments enhanced aggregation of Abeta40 (Abeta1-28, 12-28, 17-28, 10-20, 25-35 and 17-40), while three others did not (Abeta1-11, 1-16, and 20-29). All of the peptides that enhanced aggregation contained either residues 17-20 or 30-35, indicating the importance of these regions for promoting aggregation of full-length Abeta. Abeta25-35 in particular increased both the rate and extent of aggregation of Abeta40 considerably as indicated by fluorescence staining. Atomic force microscope imaging (AFM) indicates the increase in fluorescence staining with Abeta25-35 is primarily due to increased formation of oligomers and protofibrils rather than formation of large amyloid fibrils. AFM images of Abeta25-35 when incubated alone also indicate formation of aggregates and long thin filaments. The increase in formation of the small toxic oligomeric morphology of Abeta40, along with formation of Abeta25-35 oligomers and thin filaments, represent two different potential pathways for Abeta25-35 toxicity. The critical roles of residues 17-20 and 30-35 of Abeta provide further insight into mechanism that underlie the formation of toxic aggregates in Alzheimer Disease (AD) and suggest targets for the design of beta-sheet breakers to modulate the aggregation and inhibit toxicity of full-length Abeta. (C) 2003 Wiley-Liss, Inc.
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