Amyloid β fragments that suppress oligomers but not fibrils are cytoprotective

Neurotoxic aggregates of amyloid beta (Aβ) peptide contribute to the etiology of Alzheimer's disease (AD). In this work, we examined how seven overlapping fragments derived from Aβ_1-42 affect the oligomerization and toxicity of the full-length peptide. Four fragments inhibited the toxicity of oligomeric Aβ_1-42 to various degrees, two others conferred no cellular protection against Aβ_1-42 toxicity, and one fragment enhanced both Aβ_1-42 oligomerization and toxicity. The structural and aggregation propensities of the peptides that support strong inhibition of Aβ_1-42 toxicity have been identified. Data analysis allowed elucidation of the mechanisms of action of each of the seven peptide fragments on Aβ_1-42 cytotoxicity. Our work establishes the potential therapeutic value of four Aβ fragments and supports the notion that agents directed to disruption of Aβ oligomers may be more effective AD drug candidates than those targeting Aβ fibrils.