Using complementary experimental and computational techniques we have shown that non-amyloidogenic A�9-42  and  A�17-42 peptides form ion channels with loosely attached subunits and elicit single channel conductances. The emerging picture from our large-scale simulations is that toxic ion channels formed by �-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting a-helices that robustly prevent ion leakage, rather than hydrogen-bonded �-strands. Moreover, in comparison with �-rich antimicrobial peptide (AMP) such as a protegrin-1 (PG-1), both A� and PG-1 are cytotoxic, and capable of forming fibrils and dynamic channels which consist of subunits with similar dimensions. These combined properties support a functional relationship between amyloidogenic peptides and �-sheet-rich cytolytic AMPs, suggesting that PG-1 is amyloidogenic and amyloids may have an antimicrobial function.

Toxic beta-amyloid Alzheimer's ion channels: From structure to function and design

244th National Meeting (2012)

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