FIGURE 2.

Possible role of HCN channels in the generation of Aβ. Aβ is produced by two proteolytic enzymes, β- and γ-secretase. Downregulation of HCN1 channel could enhance the production of Aβ by increasing neuronal excitability in entorhinal cortex. Rats with injection of Aβ peptides into the frontal cortex exhibited decreased excitability in hippocampal pyramidal neurons, which was caused by upregulation of I_h mediated via increased HCN1. In addition, both HCN1 and HCN2 channels were able to form a complex with X11 or X11L proteins to regulate Aβ generation. The HCN2 channel can also participate in the regulation of Aβ production as a γ-secretase-associated protein, and by affecting APP maturation via modulation of the glycosylation of APP.