We examined the effects of co-incubating nine different Aβ peptide fragments with full-length Aβ1-40 (Aβ40) on protein aggregation. Six fragments enhanced aggregation of Aβ40 (Aβ1-28, 12-28, 17-28, 10-20, 25-35 and 17-40), while three others did not (Aβ1-11, 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 Aβ. Aβ25-35 in particular increased both the rate and extent of aggregation of Aβ40 considerably as indicated by fluorescence staining. Atomic force microscope imaging (AFM) indicates the increase in fluorescence staining with Aβ25-35 is primarily due to increased formation of oligomers and protofibrils rather than formation of large amyloid fibrils. AFM images of Aβ25-35 when incubated alone also indicate formation of aggregates and long thin filaments. The increase in formation of the small toxic oligomeric morphology of Aβ40, along with formation of Aβ25-35 oligomers and thin filaments, represent two different potential pathways for Aβ25-35 toxicity. The critical roles of residues 17-20 and 30-35 of Aβ provide further insight into mechanism that underlie the formation of toxic aggregates in Alzheimer Disease (AD) and suggest targets for the design of β-sheet breakers to modulate the aggregation and inhibit toxicity of full-length Aβ.
- Alzheimer's disease (AD)
- Atomic Force Microscope (AFM), cytotoxicity
- Thioflavin T (ThT)
- β-amyloid (Aβ)
- β-amyloid 25-35 (Aβ25-35)
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience