title: Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms.
abstract: The two proteases beta-secretase and gamma-secretase generate the amyloid beta peptide and are drug targets for Alzheimer's disease. Here we tested the possibility of targeting the cellular environment of beta-secretase cleavage instead of the beta-secretase enzyme itself. beta-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 beta-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 beta-secretase. Surprisingly, bepridil and amiodarone also modulated gamma-secretase cleavage independently of endosomal alkalinization. Thus, both compounds act as dual modulators that simultaneously target beta- and gamma-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.
authors.affiliation: German Center for Neurodegenerative Diseases Munich and Adolf Butenandt-Institute, Biochemistry, University of Munich, 80336 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mitterreiter
authors.forename: Richard M
authors.initials: RM
authors.lastname: Page
authors.forename: Frits
authors.initials: F
authors.lastname: Kamp
authors.forename: Jessika
authors.initials: J
authors.lastname: Hopson
authors.forename: Edith
authors.initials: E
authors.lastname: Winkler
authors.forename: Huy-Riem
authors.initials: HR
authors.lastname: Ha
authors.forename: Runa
authors.initials: R
authors.lastname: Hamid
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Mayer
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Nelson
authors.forename: Harald
authors.initials: H
authors.lastname: Steiner
authors.forename: Tobias
authors.initials: T
authors.lastname: Stahl
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zeitschel
authors.forename: Steffen
authors.initials: S
authors.lastname: Rossner
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Lichtenthaler
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000638:Amiodarone / Q000737:chemistry / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015764:Bepridil / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D015764:Bepridil; D053829:Amyloid Precursor Protein Secretases; D000638:Amiodarone