ArticleNeuropharmacology2021
Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer's disease.
Article in Neuropharmacology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 45 citations in OpenAlex.
- Endothelial C/EBPβ/AEP pathway drives vascular deterioration and systemic aging.Science advances · 2026Article
- Distinct factors drive the progression of tau pathology in Alzheimer's disease.Fundamental research · 2026Review
- BIN1 Interacts with Tau Fragments to Inhibit TrkB Signaling Endosome Recycling in a Mouse Model of Alzheimer's Disease.Neuroscience bulletin · 2026Article
- Disruption of BDNF signalling in neuropathologies.Biochemical Society transactions · 2026Review
- Exploring the Connection Between BDNF/TrkB and AC/cAMP/PKA/CREB Signaling Pathways: Potential for Neuroprotection and Therapeutic Targets for Neurological Disorders.Molecular neurobiology · 2025Review
- Asparagine endopeptidase (AEP) inhibitor formulation via zein-based nanoparticle improves the therapeutic efficacy toward Alzheimer's disease.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis.The Journal of clinical investigation · 2025Article
- The Role of Brain-Derived Neurotrophic Factor as an Essential Mediator in Neuronal Functions and the Therapeutic Potential of Its Mimetics for Neuroprotection in Neurologic and Psychiatric Disorders.Molecules (Basel, Switzerland) · 2025Review
- BDNF-TrkB Signaling in Mitochondria: Implications for Neurodegenerative Diseases.Molecular neurobiology · 2025Review
- Huanglian Wendan Decoction Improves Insomnia in Rats by Regulating BDNF/TrkB Signaling Pathway Through Gut Microbiota-Mediated SCFAs and Affecting Microglia Polarization.Molecular neurobiology · 2025Article
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- An Interaction between Brain-Derived Neurotrophic Factor and Stress-Related Glucocorticoids in the Pathophysiology of Alzheimer's Disease.International journal of molecular sciences · 2024Review
- Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening.Antioxidants (Basel, Switzerland) · 2024Article
- Multisensory Fusion Training and 7, 8-Dihydroxyflavone Improve Amyloid-β-Induced Cognitive Impairment, Anxiety, and Depression-Like Behavior in Mice Through Multiple Mechanisms.Neuropsychiatric disease and treatment · 2024Article
- Zein-Based Nanoparticles Improve the Therapeutic Efficacy of a TrkB Agonist toward Alzheimer's Disease.ACS chemical neuroscience · 2023Article
- 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
- Involvement of brain-derived neurotrophic factor signaling in the pathogenesis of stress-related brain diseases.Frontiers in molecular neuroscience · 2023Review
- The Mammalian Cysteine Protease Legumain in Health and Disease.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 3 countries.
Funding
Abstract
Alzheimer's disease (AD) is the most common dementia, and no disease-modifying therapeutic agents are currently available. BDNF/TrkB signaling is impaired in AD and is associated with prominent delta-secretase (δ-secretase, also known as asparaginyl endopeptidase or legumain) activation, which simultaneously cleaves both APP and Tau and promotes Aβ production and neurofibrillary tangles (NFT) pathologies. Here we show that the optimized δ-secretase inhibitor (#11a) or TrkB receptor agonist (CF3CN) robustly blocks δ-secretase activity separately, and their combination synergistically blunts δ-secretase, exhibiting promising therapeutic efficacy in 3xTg AD mouse model. The optimal δ-secretase inhibitor reveals demonstrable brain exposure and oral bioavailability, suppressing APP N585 and Tau N368 cleavage by δ-secretase. Strikingly, CF3CN treatment evidently escalates BDNF levels. Both #11a and CF3CN display strong in vivo PK/PD properties and ability to suppress δ-secretase activity in the brain. Orally administrated CF3CN strongly activates TrkB that triggers active Akt to phosphorylate δ-secretase T322, preventing its proteolytic activation and mitigating AD pathologies. #11a or CF3CN significantly diminishes AD pathogenesis and improves cognitive functions with the combination exhibiting the maximal effect. Thus, our data support that these derivatives are strong pharmaceutical candidates for the treatment of AD.
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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.