Architecture of the Alzheimer's AβP ion channel pore

We have proposed that the cytotoxic action of Alzheimer's amyloid beta protein might be initiated by the interaction with the neuronal cell membrane, and subsequent formation of toxic ion channels. Consequently, AbetaP toxicity can be explained on the basis of harmful ion fluxes across AbetaP channels. The conformation of AbetaP in membranes is not known. However, several models suggests that a transmembrane annular polymeric structure is responsible for the ion channel properties of the membrane-bound AbetaP. To identify that portion of the AbetaP molecule making up the conducting pore we have hypothesized that the region of the AbetaP sequence in the vicinity of the hypothetical pore might interact with complementary regions in the adjacent AbetaP subunits. We have further hypothesized that an interaction by a peptide segment would block AbetaP conductance. To test this hypothesis we synthesized peptides that encompass the histidine dyad (H-H) previously hypothesized to line the pore. We report here that peptides designed to most closely match the proposed pore are, in fact, the most effective at blocking ion currents through the membrane-incorporated AbetaP channel. As previously shown for Zn2+ blockade, peptide blockade is also asymmetric. The results also provide additional evidence for the asymmetric insertion of the AbetaP molecules into lipid membranes, and give support to the concept that rings of histidines line the entry to one side of the AbetaP pore.