Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms.
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.
Mitterreiter
Stefan
S
German Center for Neurodegenerative Diseases Munich and Adolf Butenandt-Institute, Biochemistry, University of Munich, 80336 Munich, Germany.
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Richard M
RM
Kamp
Frits
F
Hopson
Jessika
J
Winkler
Edith
E
Ha
Huy-Riem
HR
Hamid
Runa
R
Herms
Jochen
J
Mayer
Thomas U
TU
Nelson
Deborah J
DJ
Steiner
Harald
H
Stahl
Tobias
T
Zeitschel
Ulrike
U
Rossner
Steffen
S
Haass
Christian
C
Lichtenthaler
Stefan F
SF
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
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