ArticleJournal of biomedical science2026
GASDERMIN D-mediated pyroptosis as a therapeutic target in TAU-dependent frontotemporal dementia mouse model.
Article in Journal of biomedical science, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Gasdermin D in Neurodegenerative Diseases: Pathogenic Roles and Therapeutic Perspectives.Molecular neurobiology · 2026Review
- Molecular Regulation of Pyroptosis in Alzheimer's Disease: Linking Neuroinflammation, Cell Death, and Therapeutic Targeting.Molecular neurobiology · 2026Review
- The Central Role of Neuronal Cell Death in Alzheimer's Disease Pathobiology.Biomedicines · 2026Review
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Abstract
backgroundRecent research has revealed a strong connection between neuroinflammation and TAU protein-related neurodegeneration. A key discovery shows that the NLRP3 inflammasome, when activated, can significantly impact TAU pathology and subsequent neuronal death. This process involves pyroptosis, a lytic form of programmed cell death driven by inflammasome activation, leading to GASDERMIN D (GSDMD) cleavage and the subsequent release of inflammatory molecules IL-1β and IL-18. In this study, we explore the role of pyroptosis and GSDMD in Alzheimer's disease (AD) and tauopathy models, focusing on the TAU-induced neuroinflammatory process and its correlation with synaptic plasticity loss.
methodsHippocampal tissue from AD patients at Braak stage II-III has been analyzed using qPCR to assess pyroptosis-related gene expression. To determine the role of TAU in pyroptosis and neuroinflammation, we used two different models: one based on intracerebral injection of an adeno-associated virus that specifically overexpresses TAU in the neurons of the hippocampus (AAV-TAU
resultsAD patients exhibited increased expression of pyroptosis-related genes, supporting the involvement of pyroptosis in neurodegeneration. Furthermore, TAU overexpression induced pyroptosis in both mouse models, and GSDMD protein levels increased alongside reactive microglial morphology. Our data supports that TAU-induced neuroinflammation correlated with synaptic plasticity impairment. GSDMD deficiency significantly reduced pyroptosis-related markers associated to TAU, but unexpectedly worsened synaptic plasticity deficits, suggesting GSDMD may play a dual role in inflammation and synaptic function. Finally, we showed that DMF treatment suppressed pyroptosis gene expression, reduced GSDMD levels, and alleviated neuroinflammation, correlating with improved synaptic marker expression.
conclusionOur findings demonstrate that TAU-induced pyroptosis contributes to neuroinflammation and synaptic dysfunction. While GSDMD inhibition mitigates inflammation, its absence exacerbates synaptic impairment, highlighting its complex role in tauopathies. Our results indicate that DMF treatment could offer a promising therapeutic avenue to modulate pyroptosis and neuroinflammation, and restore synaptic integrity in tauopathies.
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