ArticleCurrent neuropharmacology2011
Chemical Biology, Molecular Mechanism and Clinical Perspective of γ-Secretase Modulators in Alzheimer's Disease.
Article in Current neuropharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- Smoking and increased Alzheimer's disease risk: a review of potential mechanisms.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2014Pooled it
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Novel Anti-Alzheimer's Therapeutic Molecules Targeting Amyloid Precursor Protein Processing.Oxidative medicine and cellular longevity · 2020Review
- Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481.ACS medicinal chemistry letters · 2019Article
- Precision pharmacology for Alzheimer's disease.Pharmacological research · 2018Review
- Drug candidates in clinical trials for Alzheimer's disease.Journal of biomedical science · 2017Review
- Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans.Alzheimer's research & therapy · 2015Article
- Article
- R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease.Brain research · 2013Article
- Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein.Biochemistry · 2013Article
- Development and mechanism of γ-secretase modulators for Alzheimer's disease.Biochemistry · 2013Review
- Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer's disease.PloS one · 2013Article
- Article
- Nanoparticulate flurbiprofen reduces amyloid-β42 generation in an in vitro blood-brain barrier model.Alzheimer's research & therapy · 2013Article
- Modulation of gamma-secretase for the treatment of Alzheimer's disease.International journal of Alzheimer's disease · 2012Article
- Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.
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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.