Critical role of C-terminal residues of the Alzheimer's associated ß-amyloid protein in mediating antiviral activity and modulating viral and bacterial interactions with neutrophils.

ABSTRACT

Recent studies have shown that the Alzheimer's associated ß-amyloid protein (ßA) can inhibit growth of bacteria, fungi and viruses. We reported that the 42 amino acid ßA protein inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro and modulates activation of neutrophils and monocytes exposed IAV. We here show that fragments composed of the N and C terminal domain of ßA42, including ßA22-42 and the 8 amino acid ßA35-42, retain viral neutralizing and viral aggregating activity, whereas fragments lacking the C-terminal amino acids 41 and 42 (e.g. ßA1-40, ßA1-34, ßA1-28, ßA22-40 or ßA33-40) have markedly diminished activities on these assays. ßA22-42 also increased viral uptake, and virus induced respiratory burst responses, by human neutrophils, while peptides lacking residues 41 and 42 did not. Similar results were obtained with regard to bacterial aggregation, or promotion of bacterial uptake by neutrophils. Published structural studies have shown that ßA1-42 has a greater propensity to form neurotoxic oligomers than ßA1-40 due to a molecular interaction between Met35 and Ala42. Our findings suggest that there is a relationship between neurotoxic and antimicrobial activities of ßA1-42. Truncated peptides containing the last 8 C-terminal amino acids of ßA1-42 retain antimicrobial and opsonizing activities likely resulting from their ability to induce viral or bacterial aggregation.