ArticleJCI insight2018
BDNF inhibits neurodegenerative disease-associated asparaginyl endopeptidase activity via phosphorylation by AKT.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- Food Timing, Circadian Rhythm and Chrononutrition: A Systematic Review of Time-Restricted Eating's Effects on Human Health.Nutrients · 2020Pooled it
- Advances in Alzheimer's disease: mechanistic insights and therapeutic targets.Science China. Life sciences · 2026Review
- Neuroinflammation and Secretase Regulation in Alzheimer's Disease: From Molecular Cross-Talk to Multi-Target Therapeutics.International journal of molecular sciences · 2026Review
- C/EBPβ dictates postmenopausal FSHβ transcription and blockade of AEP/C/EBPβ pathway alleviates osteoporosis.Bone research · 2026Article
- BIN1 Interacts with Tau Fragments to Inhibit TrkB Signaling Endosome Recycling in a Mouse Model of Alzheimer's Disease.Neuroscience bulletin · 2026Article
- Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer's disease.Nature communications · 2025Article
- SG06, a Chalcone Derivative Targets PI3K/AKT1 Pathway for Neuroprotection and Cognitive Enhancement in an Alzheimer's Disease-Like Zebrafish Model.Molecular neurobiology · 2025Article
- Immunotherapy against tau fragment diminishes AD pathology, improving synaptic function and cognition.Molecular neurodegeneration · 2025Article
- CDO1 phosphorylation is required for IL-6-induced tumor cell proliferation through governing cysteine availability.Cell communication and signaling : CCS · 2025Article
- BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases.Molecular neurobiology · 2025Review
- GDF1 ameliorates cognitive impairment induced by hearing loss.Nature aging · 2024Article
- Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- Mechanisms of the Beneficial Effects of Exercise on Brain-Derived Neurotrophic Factor Expression in Alzheimer's Disease.Biomolecules · 2023Review
- Zein-Based Nanoparticles Improve the Therapeutic Efficacy of a TrkB Agonist toward Alzheimer's Disease.ACS chemical neuroscience · 2023Article
- C/EBPβ/AEP Signaling Drives Alzheimer's Disease Pathogenesis.Neuroscience bulletin · 2023Review
- Pharmacological Inhibition of the Asparaginyl Endopeptidase (AEP) in an Alzheimer's Disease Model Improves the Survival and Efficacy of Transplanted Neural Stem Cells.International journal of molecular sciences · 2023Article
- Temperature- and chemical-induced neurotoxicity in zebrafish.Frontiers in physiology · 2023Review
- A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin.Nature communications · 2022Article
- Treating Parkinson's Disease via Activation of BDNF/TrkB Signaling Pathways and Inhibition of Delta-Secretase.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
- Mammalian AKT, the Emerging Roles on Mitochondrial Function in Diseases.Aging and disease · 2022Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
AEP is an age-dependent lysosomal asparaginyl endopeptidase that cleaves numerous substrates including tau and α-synuclein and mediates their pathological roles in neurodegenerative diseases. However, the molecular mechanism regulating this critical protease remains incompletely understood. Here, we show that Akt phosphorylates AEP on residue T322 upon brain-derived neurotrophic factor (BDNF) treatment and triggers its lysosomal translocation and inactivation. When BDNF levels are reduced in neurodegenerative diseases, AEP T322 phosphorylation is attenuated. Consequently, AEP is activated and translocates into the cytoplasm, where it cleaves both tau and α-synuclein. Remarkably, the unphosphorylated T322A mutant increases tau or α-synuclein cleavage by AEP and augments cell death, whereas phosphorylation mimetic T322E mutant represses these effects. Interestingly, viral injection of T322E into Tau P301S mice antagonizes tau N368 cleavage and tau pathologies, rescuing synaptic dysfunction and cognitive deficits. By contrast, viral administration of T322A into young α-SNCA mice elicits α-synuclein N103 cleavage and promotes dopaminergic neuronal loss, facilitating motor defects. Therefore, our findings support the notion that BDNF contributes to the pathogenesis of neurodegenerative diseases by suppressing AEP via Akt phosphorylation.
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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.