Aβ1-16 Can Aggregate and Induce the Production of Reactive Oxygen Species, Nitric Oxide, and Inflammatory Cytokines

Amyloid-beta (A beta(40/42)) aggregates containing the cross-beta-sheet structure are associated with the pathogenesis of Alzheimer's disease (AD). It is generally accepted that the N-terminal peptide of A beta(40/42), A beta(1-16), does not aggregate, and is not cytotoxic. However, we here show that A beta(1-16) can aggregate, and form cytotoxic aggregates containing beta-turns and regular non-amyloid beta-sheet structures. Factors such as pH, ionic strength, and agitation were found to influence A beta(1-16) aggregation, and the amino acid residues Asp1, His6, Ser8, and Val12 in A beta(1-16) may play a role in this aggregation. Our MTT results showed that A beta(1-16) monomers or oligomers were toxic to SH-SY5Y cells, but A beta(1-16) fibrils exhibited less cytotoxicity. Our studies also indicate that A beta(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-alpha and IL-4. Thus, our findings suggest that A beta(1-16) may contribute to AD pathogenesis.