All-D-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers

Alzheimer's disease (AD) is the most common type of senile dementia in aging populations. Amyloid beta (A beta)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. A beta-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via A beta binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an A beta peptide enantiomer, whose entire sequence consists of D-amino acids, can form ion-conducting channels; these channels can directly mediate A beta effects even in the absence of receptor peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we.;how that the (L)-A beta isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the (L)-A beta isomer. The D isomer forms channel-like pores with heterogeneous ionic conductance similar to the (L)-A beta isomer channels, and the D-isomer channel conductance is blocked by Zn2+, a known blocker of L-A beta isomer channels. MD simulations further verify formation of beta-barrel. like A beta channels with D- and L-isomers, illustrating that both D- and L-A beta barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that A beta toxicity is mediated through a receptor-independent, nonstereoselective mechanism.