The publication detail shows the title, authors (with indicators showing other profiled authors), information on the publishing organization, abstract and a link to the article in PubMed. This abstract is what is used to create the fingerprint of the publication. If any grants are referenced by the publication, they will be listed here as well.
Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms.
Stefan Mitterreiter; Richard M Page; Frits Kamp; Jessika Hopson; Edith Winkler; Huy-Riem Ha; Runa Hamid; Jochen Herms; Thomas U Mayer; Deborah J Nelson; et al. (Profiled Author: Haass, Christian)
German Center for Neurodegenerative Diseases Munich and Adolf Butenandt-Institute, Biochemistry, University of Munich, 80336 Munich, Germany.
The Journal of neuroscience : the official journal of the Society for Neuroscience 2010;30(26):8974-83.
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.
This section shows information related to the publication - computed using the fingerprint of the publication - including related publications, related experts and related grants with fingerprints representing significant amounts of overlap between their fingerprint and this publication. The red dots indicate whether those experts or terms appear within the publication, thereby showing potential and actual connections.
TANZI, RUDOLPH EMILE
30 September 2012 - 31 August 2017
NATIONAL INSTITUTE ON AGING
Total Funding: $ 345,936
Golde, Todd E
10 April 2000 - 30 April 2009
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Total Funding: $ 2,532,291
Gandy, Samuel E
1 September 2005 - 30 June 2008
NATIONAL INSTITUTE ON AGING
Total Funding: $ 898,167
Hiroaki Fukumoto; Hideki Takahashi; Naoki Tarui; Junji Matsui; Taisuke Tomita; Mitsuhiro Hirode; Masumi Sagayama; Ryouta Maeda; Makiko Kawamoto; Kazuko Hirai; et al.The Journal of neuroscience : the official journal of the Society for Neuroscience 2010;30(33):11157-66.
Saravanan S Karuppagounder; Hui Xu; Qingli Shi; Lian H Chen; Steve Pedrini; David Pechman; Harriet Baker; M Flint Beal; Sam E Gandy; Gary E GibsonNeurobiology of aging 2009;30(10):1587-600.
Thor D Stein; Nicholas J Anders; Charles DeCarli; Sic L Chan; Mark P Mattson; Jeffrey A Johnson
Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis.The Journal of neuroscience : the official journal of the Society for Neuroscience 2004;24(35):7707-17.
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