RT Journal Article
SR Electronic
T1 Bepridil and Amiodarone Simultaneously Target the Alzheimer's Disease β- and γ-Secretase via Distinct Mechanisms
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8974
OP 8983
DO 10.1523/JNEUROSCI.1199-10.2010
VO 30
IS 26
A1 Stefan Mitterreiter
A1 Richard M. Page
A1 Frits Kamp
A1 Jessika Hopson
A1 Edith Winkler
A1 Huy-Riem Ha
A1 Runa Hamid
A1 Jochen Herms
A1 Thomas U. Mayer
A1 Deborah J. Nelson
A1 Harald Steiner
A1 Tobias Stahl
A1 Ulrike Zeitschel
A1 Steffen Roßner
A1 Christian Haass
A1 Stefan F. Lichtenthaler
YR 2010
UL http://www.jneurosci.org/content/30/26/8974.abstract
AB The two proteases β-secretase and γ-secretase generate the amyloid β peptide 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.