Bepridil and amiodarone simultaneously target the Alzheimer's disease β- and γ-secretase via distinct mechanisms

The two proteases β-secretase and γ-secretase generate the amyloid βpeptide and are drug targets for Alzheimer's disease. Here we tested the possibility of targeting the cellular environment of β-secretase cleavage instead of the β-secretase enzyme itself. β-Secretase has an acidic pH optimum and cleaves the amyloid precursor protein in the acidic endosomes. We identified two drugs, bepridil and amiodarone, that are weak bases and are in clinical use as calcium antagonists. Independently of their calcium-blocking activity, both compounds mildly raised the membrane-proximal, endosomal pH and inhibited β-secretase cleavage at therapeutically achievable concentrations in cultured cells, in primary neurons, and in vivo in guinea pigs. This shows that an alkalinization of the cellular environment could be a novel therapeutic strategy to inhibit β-secretase. Surprisingly, bepridil and amiodarone also modulated γ-secretase cleavage independently of endosomal alkalinization. Thus, both compounds act as dual modulators that simultaneously target β- and γ-secretase through distinct molecular mechanisms. In addition to Alzheimer's disease, compounds with dual properties may also be useful for drug development targeting other membrane proteins.