ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers, 1 of them a synthesis that pooled it.
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Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- Histone deacetylase-mediated regulation of endolysosomal pH.The Journal of biological chemistry · 2018Pooled it
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- Drug repurposing for neurodegenerative diseases using Zebrafish behavioral profiles.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2024Article
- Selection of lansoprazole from an FDA-approved drug library to inhibit the Alzheimer's disease seed-dependent formation of tau aggregates.Frontiers in aging neuroscience · 2024Article
- The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.Molecular neurodegeneration · 2023Article
- Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases.Reviews of physiology, biochemistry and pharmacology · 2023Article
- Hippocampal Degeneration and Behavioral Impairment During Alzheimer-Like Pathogenesis Involves Glutamate Excitotoxicity.Journal of molecular neuroscience : MN · 2021Article
- Bepridil is potent against SARS-CoV-2 in vitro.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Emerging links between endosomal pH and cancer.Cancer metastasis reviews · 2020Review
- Blockade of the forward NaBritish journal of pharmacology · 2019Article
- NrCAM is a marker for substrate-selective activation of ADAM10 in Alzheimer's disease.EMBO molecular medicine · 2019Article
- Interactions of Aromatase and Seladin-1: A Neurosteroidogenic and Gender Perspective.Translational neuroscience · 2019Article
- The Calcium Channel Blocker Bepridil Demonstrates Efficacy in the Murine Model of Marburg Virus Disease.The Journal of infectious diseases · 2018Article
- Autophagy stimulation as a promising approach in treatment of neurodegenerative diseases.Metabolic brain disease · 2018Review
- Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments.The EMBO journal · 2018Review
- Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Antiviral activity of cationic amphiphilic drugs.Expert review of anti-infective therapy · 2017Review
- Functions of the Alzheimer's Disease Protease BACE1 at the Synapse in the Central Nervous System.Journal of molecular neuroscience : MN · 2016Review
- Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.Molecular neurodegeneration · 2016Article
- Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein-specific antibodies.Aging cell · 2016Article
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 5 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.