Bepridil and Amiodarone Simultaneously Target the Alzheimer's Disease  - and  -Secretase via Distinct Mechanisms

Abstract

The two proteases ␤-secretase and ␥-secretase generate the amyloid ␤ peptide and are drug targets for Alzheimer's disease. Here we tested the possibility of targeting the cellular environment of ␤-secretase cleavage instead of the ␤-secretase enzyme itself. ␤-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 ␤-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 ␤-secretase. Surprisingly, bepridil and amiodarone also modulated ␥-secretase cleavage independently of endosomal alkalinization. Thus, both compounds act as dual modulators that simultaneously target ␤-and ␥-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.

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

“…All animal experiments were performed according to the European community council directive (86/609/ECC). Neurons were isolated as described previously (Mitterreiter et al ., 2010) at E15/E16 and cultured in neurobasal medium supplemented with 2% B27, 100 U mL −1 penicillin, 100 μg mL −1 streptomycin and 0.5 m m glutamine. Experiments were carried out after 4–7 days in vitro (DIV).…”

The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease

“…We suggest that therapeutic elevation of endosomal pH using mildly alkalinizing drugs or by enhancing NHE6 activity will significantly reduce amyloid and Tau pathologies. For example, the weak bases bepridil and amiodarone, already in clinical use as calcium antagonists, were shown to mildly alkalinize endosomes and inhibit cleavage by ␤-secretase in cultured cells, in neurons, and in an in vivo guinea pig model (73). Membrane transporters like NHE6 are eminently "druggable targets" for Alzheimer disease and other neurological disorders that share endosomal dysfunction and trafficking defects.…”

Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase

“…Both drugs are weak bases and are clinically used for treatment of angina pectoris or arrhythmias (Hollingshead et al, 1992;Siddoway, 2003). Moreover, both drugs were shown recently to modulate amyloid ␤-peptide production (Mitterreiter et al, 2010). When the above described lymphoblast cells from healthy controls and FTLD-TDP patients carrying a GRN lossof-function mutation were treated with bepridil or amiodarone, both drugs significantly increased GRN levels in conditioned media (Fig.…”