Residues 17–20 and 30–35 of beta‐amyloid play critical roles in aggregation

Abstract

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.