ArticleMolecular psychiatry2022
Caspase-cleaved tau is senescence-associated and induces a toxic gain of function by putting a brake on axonal transport.
Article in Molecular psychiatry, 2022. 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.
- Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2026Review
- Dissecting Structural and Functional Determinants of Microtubules Stabilization through Guided Chemical Modulation.Journal of medicinal chemistry · 2026Article
- Microglia-mediated synaptic pruning in neural circuit remodeling: multidimensional control in homeostasis and neuropathology.BMC medicine · 2026Review
- The role of 2-Oxoglutarate dehydrogenase complex mitochondrial enzyme in alzheimer's disease: a literature review and bioinformatics workflow.Metabolic brain disease · 2026Review
- Amyloid β Instigates Cardiac Neurotrophic Signaling Impairment, Driving Alzheimer's Associated Heart Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Beyond microtubule regulation: the multifaceted roles of tau in neuronal function and dysfunction.Translational psychiatry · 2026Review
- A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons.bioRxiv : the preprint server for biology · 2026Article
- Pretangle tau pathology accrual in the default mode network during the progression of Alzheimer's disease.Molecular neurodegeneration advances · 2026Article
- Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer's disease.Nature communications · 2025Article
- Synthetic chaperone based on Hsp90-Tau interaction inhibits Tau aggregation and rescues physiological Tau-Microtubule interaction.Nature communications · 2025Article
- Cyclophilin D (CypD) ablation prevents neurodegeneration and cognitive damage induced by caspase-3 cleaved tau.Free radical biology & medicine · 2025Article
- Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Review
- MAPT mutations in amyotrophic lateral sclerosis: clinical, neuropathological and functional insights.Journal of neurology · 2025Article
- Article
- Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau.The Journal of clinical investigation · 2025Article
- Decoding the role of microtubules: a trafficking road for vesicle.Theranostics · 2025Review
- Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP.Nature communications · 2024Article
- Sleep-wake body temperature regulates tau secretion in mice and correlates with CSF and plasma tau in humans.Research square · 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
- Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction.Nature communications · 2024Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The microtubule-associated protein tau plays a central role in tauopathies such as Alzheimer's disease (AD). The exact molecular mechanisms underlying tau toxicity are unclear, but aging is irrefutably the biggest risk factor. This raises the question of how cellular senescence affects the function of tau as a microtubule regulator. Here we report that the proportion of tau that is proteolytically cleaved at the caspase-3 site (TauC3) doubles in the hippocampus of senescent mice. TauC3 is also elevated in AD patients. Through quantitative live-cell imaging, we show that TauC3 has a drastically reduced dynamics of its microtubule interaction. Single-molecule tracking of tau confirmed that TauC3 has a longer residence time on axonal microtubules. The reduced dynamics of the TauC3-microtubule interaction correlated with a decreased transport of mitochondria, a reduced processivity of APP-vesicle transport and an induction of region-specific dendritic atrophy in CA1 neurons of the hippocampus. The microtubule-targeting drug Epothilone D normalized the interaction of TauC3 with microtubules and modulated the transport of APP-vesicles dependent on the presence of overexpressed human tau. The results indicate a novel toxic gain of function, in which a post-translational modification of tau changes the dynamics of the tau-microtubule interaction and thus leads to axonal transport defects and neuronal degeneration. The data also introduce microtubule-targeting drugs as pharmacological modifiers of the tau-microtubule interaction with the potential to restore the physiological interaction of pathologically altered tau with microtubules.
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