ArticleMolecular psychiatry2021
TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer's disease.Molecular neurodegeneration · 2022Pooled it
- Disruption of BDNF signalling in neuropathologies.Biochemical Society transactions · 2026Review
- Rebalancing NTRK2 isoforms promotes vascular regeneration in bronchopulmonary dysplasia.Cell stem cell · 2026Article
- The Intricate Relationship of Trk Receptors in Brain Diseases and Disorders.Molecular neurobiology · 2025Review
- Serum BDNF and progression to MCI in cognitively normal older adults: A prospective cohort study.The journal of prevention of Alzheimer's disease · 2025Article
- Immunotherapy against tau fragment diminishes AD pathology, improving synaptic function and cognition.Molecular neurodegeneration · 2025Article
- Isoform-Specific Roles of NTRK2 in Pulmonary Vascular Regeneration.bioRxiv : the preprint server for biology · 2025Article
- N-terminomics profiling of naïve and inflamed murine colon reveals proteolytic signatures of legumain.Journal of cellular physiology · 2025Article
- Viral vectors in neurodegenerative diseases: immune responses and therapeutic applications.Frontiers in neurology · 2025Review
- Targeting brain-derived neurotrophic factor in the treatment of neurodegenerative diseases: A review.Neuroprotection (Chichester, England) · 2024Review
- Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- Phosphoproteome Microarray Analysis of Extracellular Particles as a Tool to Explore Novel Biomarker Candidates for Alzheimer's Disease.International journal of molecular sciences · 2024Article
- Chemical Tools to Image the Activity of PAR-Cleaving Proteases.ACS bio & med chem Au · 2023Review
- C/EBPβ/AEP Signaling Drives Alzheimer's Disease Pathogenesis.Neuroscience bulletin · 2023Review
- Thrombospondin1 mimics rapidly relieve depression via Shank3 dependent uncoupling between dopamine D1 and D2 receptors.iScience · 2023Article
- Exploiting machine learning models to identify novel Alzheimer's disease biomarkers and potential targets.Scientific reports · 2023Review
- Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators.International journal of molecular sciences · 2022Article
- Amyloid Cascade Hypothesis for the Treatment of Alzheimer's Disease: Progress and Challenges.Aging and disease · 2022Article
- Psychedelic-inspired approaches for treating neurodegenerative disorders.Journal of neurochemistry · 2022Review
- Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential.Translational neurodegeneration · 2022Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
Neurotrophins promote neuronal survival and synaptic plasticity via activating the tropomyosin receptor kinases. BDNF and its high-affinity receptor TrkB are reduced in Alzheimer's disease (AD), contributing to progressive cognitive decline. However, how the signaling mediates AD pathologies remains incompletely understood. Here we show that the TrkB receptor binds and phosphorylates APP, reducing amyloid-β production, which are abrogated by δ-secretase cleavage of TrkB in AD. Remarkably, BDNF stimulates TrkB to phosphorylate APP Y687 residue that accumulates APP in the TGN (Trans-Golgi Network) and diminishes its amyloidogenic cleavage. Delta-secretase cleaves TrkB at N365 and N486/489 residues and abolishes its neurotrophic activity, decreasing p-APP Y687 and altering its subcellular trafficking. Notably, both TrkB and APP are robustly cleaved by δ-secretase in AD brains, accompanied by mitigated TrkB signaling and reduced p-Y687. Blockade of TrkB cleavage attenuates AD pathologies in 5xFAD mice, rescuing the learning and memory. Viral expression of TrkB 1-486 fragment in the hippocampus of APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis.
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Registered trials
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