ArticleNeuropathology and applied neurobiology2022
Caspase-6-cleaved tau is relevant in Alzheimer's disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications.
Article in Neuropathology and applied neurobiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 23 citations in OpenAlex.
- Attenuation of Tau Hyperphosphorylation by Chronic Toxoplasma gondii Infection in a Mouse Model of Alzheimer's Disease.Parasite immunology · 2026Article
- Six promising drug repurposing candidates for Alzheimer's disease and their sex-specific mechanisms and efficacy.Neural regeneration research · 2026Article
- The Intricate Role of Caspase-6 and Death Receptor-6 in Neurodegenerative Diseases.Cell biochemistry and biophysics · 2026Review
- Optimized detection of caspase-6 activation in a murine inflammation model to inform neurodegenerative disease therapies.PloS one · 2026Article
- Post-translational modifications as a regulatory code for tau function in health and disease.Frontiers in dementia · 2026Review
- Alzheimer's disease: insights into pathology, molecular mechanisms, and therapy.Protein & cell · 2025Review
- Targeting necroptosis in Alzheimer's disease: can exercise modulate neuronal death?Frontiers in aging neuroscience · 2025Review
- An NMR sample preparation case study: Considerations for the self-destructive protease caspase-6.PloS one · 2025Article
- iPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death.Molecular and cellular neurosciences · 2024Article
- Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer's disease: implications for biomarker development and therapeutic targeting.Acta neuropathologica communications · 2024Review
- Article
- Indoxyl sulfate induces apoptosis in mononuclear blood cells via mitochondrial pathway.Scientific reports · 2023Article
- Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity.iScience · 2023Article
- Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6.Journal of the American Chemical Society · 2023Article
- Disruption of protein geranylgeranylation in the cerebellum causes cerebellar hypoplasia and ataxia via blocking granule cell progenitor proliferation.Molecular brain · 2023Article
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Authors and funding
19 authors at 4 institutions in 3 countries.
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Abstract
aimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet the relationship between aCasp-6, different forms of tr-tau and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear.
methodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies.
resultsCasp-6 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies.
conclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.
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