Aβ 1-16 Can Aggregate and Induce the Production of Reactive Oxygen Species,Nitric Oxide,and Inflammatory Cytokines

Abstract

Amyloid-β (Aβ_40/42) aggregates containing the cross-β-sheet structure are associated with the pathogenesis of Alzheimer's disease (AD). It is generally accepted that the N-terminal peptide of Aβ_40/42, Aβ_1-16, does not aggregate, and is not cytotoxic. However, we here show that Aβ_1-16 can aggregate, and form cytotoxic aggregates containing β-turns and regular non-amyloid β-sheet structures. Factors such as pH, ionic strength, and agitation were found to influence Aβ_1-16 aggregation, and the amino acid residues Asp1, His6, Ser8, and Val12 in Aβ_1-16 may play a role in this aggregation. Our MTT results showed that Aβ_1-16 monomers or oligomers were toxic to SH-SY5Y cells, but Aβ_1-16 fibrils exhibited less cytotoxicity. Our studies also indicate that Aβ_1-16 aggregates can increase the formation of reactive oxygen species and nitric oxide, induce the loss of calcium homeostasis, and incur the microglial production of TNF-α and IL-4. Thus, our findings suggest that Aβ_1-16 may contribute to AD pathogenesis.