Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies
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Significance: BDNF is important in neuronal survival and synaptic plasticity. BDNF level reduction in Alzheimer’s disease (AD) is well documented, but it remains unclear whether BDNF deficiency contributes to AD pathology. We show that BDNF deprivation provokes asparagine endopeptidase (AEP) activation via reducing δ-secretase (AEP) T322 phosphorylation by Akt and subsequently cleaves Tau at N368 residue and enhances its binding with TrkB receptors, blocking the neurotrophic signals. Our data demonstrate that AEP-cleaved Tau N368 interacting with TrkB might account for BDNF reduction-triggered AD pathologies.
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Weakened BDNF signaling triggers activation of JAK2/STAT3 and C/EBPβ signaling pathways in the AD brain and inhibits downstream Akt signaling molecules, thereby promoting activation of asparagine endopeptidase to cleave APP and tau proteins.
“This weakened signaling triggers the activation of JAK2/STAT3 and C/EBPβ signaling pathways in the AD brain and inhibits downstream Akt signaling molecules,349 thereby promoting the activation of asparagine endopeptidase (AEP; also called δ-secretase) to cleave APP and tau proteins.350,351”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [349]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredCleaved tau fragments can bind to TrkB receptors, further inducing neuronal apoptosis.
“The cleaved tau fragments could bind to TrkB receptors, further inducing neuronal apoptosis.349”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [349]
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- Authors
- Xiang, J., Wang, Z.-H., Ahn, E. H., Liu, X., Yu, S.-P., Manfredsson, F. P., Sandoval, I. M., Ju, G., Wu, S., & Ye, K.
- Affiliations
- Emory University (US)
- Michigan State University (US)
- Air Force Medical University (CN)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-04-17
- Volume
- 116
- Issue
- 18
- Pages
- 9094-9102
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6500177
- OpenAlex
- W2936022182
- Cited by
- 67
- References
- 40
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 8 · 2023: 11 · 2022: 13 · 2021: 10 · 2020: 11 · 2019: 1 · 2018: 1
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute on Aging (AG051538)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, brain-derived neurotrophic factor, TrkB receptor, asparaginyl endopeptidase, tau cleavage, neurotrophic signaling, neuronal cell death, Akt phosphorylation, cognitive impairment
- MeSH terms
- Asparaginyl Endopeptidase, Alzheimer Disease, Animals, Brain, Cell Line, Cognition, Cysteine Endopeptidases, Female, Humans, Male, Mice, Inbred C57BL, Neurons, Phosphorylation, Signal Transduction, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Brain-Derived Neurotrophic Factor, Receptor, trkB, Proto-Oncogene Proteins c-akt, Mice, Amyloid Precursor Protein Secretases, Cognitive Dysfunction, Primary Cell Culture
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