ArticleClinical and translational medicine2022
P301S-hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau-induced synaptic toxicities.
Article in Clinical and translational medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 18 citations in OpenAlex.
- Review
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- Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.Redox biology · 2025Review
- GLSP mitigates vascular aging by promoting Sirt7-mediated Keap1 deacetylation and Keap1-Nrf2 dissociation.Theranostics · 2025Article
- Role of NRF2 in Pathogenesis of Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2024Review
- Impairment of Nrf2 signaling in the hippocampus of P301S tauopathy mice model aligns with the cognitive impairment and the associated neuroinflammation.Journal of inflammation (London, England) · 2024Article
- Tau induces inflammasome activation and microgliosis through acetylating NLRP3.Clinical and translational medicine · 2024Article
- Gallic Acid Alleviates Cognitive Impairment by Promoting Neurogenesis via the GSK3β-Nrf2 Signaling Pathway in an APP/PS1 Mouse Model.Journal of Alzheimer's disease reports · 2024Article
- Exosomal SOX21-AS1 Regulates EREG by Sponging miR-451a and Promotes the Malignancy of Pancreatic Ductal Adenocarcinoma.Journal of Cancer · 2024Article
- The emerging nontraditional roles for tau in the brain.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Aging, NRF2, and TAU: A Perfect Match for Neurodegeneration?Antioxidants (Basel, Switzerland) · 2023Review
- Slingshot homolog-1-mediated Nrf2 sequestration tips the balance from neuroprotection to neurodegeneration in Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Therapeutic potential ofFrontiers in pharmacology · 2023Article
- P301S-hTau acetylates KEAP1 to trigger synaptic toxicity via inhibiting NRF2/ARE pathway: A novel mechanism underlying hTau-induced synaptic toxicities.Clinical and translational medicine · 2022Article
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Authors and funding
11 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundHuman Tau (hTau) accumulation and synapse loss are two pathological hallmarks of tauopathies. However, whether and how hTau exerts toxic effects on synapses remain elusive.
methodsMutated hTau (P301S) was overexpressed in the N2a cell line, primary hippocampal neurons and hippocampal CA3. Western blotting and quantitative polymerase chain reaction were applied to examine the protein and mRNA levels of synaptic proteins. The protein interaction was tested by co-immunoprecipitation and proximity ligation assays. Memory and emotion status were evaluated by a series of behavioural tests. The transcriptional activity of nuclear factor-erythroid 2-related factor 2 (NRF2) was detected by dual luciferase reporter assay. Electrophoresis mobility shift assay and chromosome immunoprecipitation were conducted to examine the combination of NRF2 to specific anti-oxidative response element (ARE) sequences. Neuronal morphology was analysed after Golgi staining.
resultsOverexpressing P301S decreased the protein levels of post-synaptic density protein 93 (PSD93), PSD95 and synapsin 1 (SYN1). Simultaneously, NRF2 was decreased, whereas Kelch-like ECH-associated protein 1 (KEAP1) was elevated. Further, we found that NRF2 could bind to the specific AREs of DLG2, DLG4 and SYN1 genes, which encode PSD93, PSD95 and SYN1, respectively, to promote their expression. Overexpressing NRF2 ameliorated P301S-reduced synaptic proteins and synapse. By means of acetylation at K312, P301S increased the protein level of KEAP1 via inhibiting KEAP1 degradation from ubiquitin-proteasome pathway, thereby decreasing NRF2 and reducing synapse. Blocking the P301S-KEAP1 interaction at K312 rescued the P301S-suppressed expression of synaptic proteins and memory deficits with anxiety efficiently.
conclusionsP301S-hTau could acetylate KEAP1 to trigger synaptic toxicity via inhibiting the NRF2/ARE pathway. These findings provide a novel and potential target for the therapeutic intervention of tauopathies.
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