ArticleCell discovery2015
Targeting the γ-/β-secretase interaction reduces β-amyloid generation and ameliorates Alzheimer's disease-related pathogenesis.
Article in Cell discovery, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
- Role of GSK-3 Inhibition in Alzheimer's Disease Therapy.Current Alzheimer research · 2026Review
- Proposed Therapeutic Strategy to Combat Alzheimer's Disease by Targeting Beta and Gamma Secretases.Current Alzheimer research · 2025Review
- In silico and in vitro analyses of a novel FoxO1 agonist reducing Aβ levels via downregulation of BACE1.CNS neuroscience & therapeutics · 2024Article
- PS1 Affects the Pathology of Alzheimer's Disease by Regulating BACE1 Distribution in the ER and BACE1 Maturation in the Golgi Apparatus.International journal of molecular sciences · 2022Article
- Concatenation of molecular docking and molecular simulation of BACE-1, γ-secretase targeted ligands: in pursuit of Alzheimer's treatment.Annals of medicine · 2021Article
- Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity.Biomolecules · 2021Article
- Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature.RSC advances · 2020Article
- Antagonism of cysteinyl leukotrienes and their receptors as a neuroinflammatory target in Alzheimer's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2020Review
- Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/γ-secretase at the cell surface.eLife · 2020Article
- The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization.International journal of molecular sciences · 2020Article
- Recent Trends in the Management of Alzheimer's Disease: Current Therapeutic Options and Drug Repurposing Approaches.Current neuropharmacology · 2020Review
- Modulation of Amyloid-β42 Conformation by Small Molecules Through Nonspecific Binding.Journal of chemical theory and computation · 2019Article
- A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.The Journal of cell biology · 2019Article
- ALWPs Improve Cognitive Function and Regulate Aβ Plaque and Tau Hyperphosphorylation in a Mouse Model of Alzheimer's Disease.Frontiers in molecular neuroscience · 2019Article
- Visualization of Alzheimer's Disease Related α-/β-/γ-Secretase Ternary Complex by Bimolecular Fluorescence Complementation Based Fluorescence Resonance Energy Transfer.Frontiers in molecular neuroscience · 2018Article
- Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism.BioMed research international · 2018Review
- Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease.Frontiers in neuroscience · 2018Article
- Fraction n-Butanol of Radix Notoginseng Protects PC12 Cells from AEvidence-based complementary and alternative medicine : eCAM · 2017Article
- Article
- An Anti-Parkinson's Disease Drug via Targeting Adenosine A2A Receptor Enhances Amyloid-β Generation and γ-Secretase Activity.PloS one · 2016Article
Corrections and comments
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Authors and funding
12 authors at 7 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite decades of intense global effort, no disease-modifying drugs for Alzheimer's disease have emerged. Molecules targeting catalytic activities of γ-secretase or β-site APP-cleaving enzyme 1 (BACE1) have been beset by undesired side effects. We hypothesized that blocking the interaction between BACE1 and γ-secretase subunit presenilin-1 (PS1) might offer an alternative strategy to selectively suppress Aβ generation. Through high-throughput screening, we discovered that 3-α-akebonoic acid (3AA) interferes with PS1/BACE1 interaction and reduces Aβ production. Structural analogs of 3AA were systematically synthesized and the functional analog XYT472B was identified. Photo-activated crosslinking and biochemical competition assays showed that 3AA and XYT472B bind to PS1, interfere with PS1/BACE1 interaction, and reduce Aβ production, whereas sparing secretase activities. Furthermore, treatment of APP/PS1 mice with XYT472B alleviated cognitive dysfunction and Aβ-related pathology. Together, our results indicate that chemical interference of PS1/BACE1 interaction is a promising strategy for Alzheimer's disease therapeutics.
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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.