ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC-derived neurons to amyloid beta and phosphorylated tau-induced neuronal dysfunction.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed.
- Targeting TTLL1 Alleviates Aβ-Induced Microtubule Disruption and TAU Pathology in Human iPSC-Derived Cortical Neurons.Pharmaceutics · 2026Article
- Tau dysfunction in alzheimer's disease: molecular and cellular mechanisms, genetic modulation, and therapeutic perspectives.Molecular biology reports · 2026Review
- MAPT -isoform 0N3R is essential for human brain development: Loss-of-function for novel TAU-associated disease paradigms.Neural regeneration research · 2026Article
- The mechanisms and strategies for Alzheimer's disease prevention: An update.Acta pharmaceutica Sinica. B · 2026Review
- Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer's disease.Acta neuropathologica · 2026Article
- CRISPR Applications in Alzheimer's Disease: From High-Throughput Genetic Screening to Precision Editing and CNS Delivery.International journal of molecular sciences · 2026Review
- Axon Initial Segment: Structure, Biological Functions, Diseases, and Therapeutic Targets.MedComm · 2026Review
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Drosophila wing is a high-throughput and versatile screening tool for Tau-mediated disease mechanisms and drug discovery.Disease models & mechanisms · 2026Article
- Multi-omic phenotyping of MAPT V337M neurons reveals early changes in axonogenesis and tau phosphorylation.NPJ dementia · 2026Article
- Recent molecular insights and biosensor-based diagnostic technologies for hyperphosphorylated Tau in Alzheimer's disease.Alzheimer's research & therapy · 2025Review
- Tau Axonal Sorting and Interaction With Synaptic Plasticity Modulators Is Domain- and Isoform-Dependent in Human iPSC-Derived Neurons.Aging cell · 2025Article
- Multi-omic phenotyping of iPSC-derived neurons harboring thebioRxiv : the preprint server for biology · 2025Article
- CRISPR/Cas9 and iPSC-Based Therapeutic Approaches in Alzheimer's Disease.Antioxidants (Basel, Switzerland) · 2025Review
- The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC-derived neurons to amyloid beta and phosphorylated tau-induced neuronal dysfunction.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Mechanical stimulation prevents impairment of axon growth and overcompensates microtubule destabilization in cellular models of Alzheimer's disease and related Tau pathologies.Frontiers in medicine · 2025Article
- Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons.Neural regeneration research · 2024Article
- The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Review
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12 authors.
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Abstract
introductionHuman tau protein, composed of six brain-specific isoforms, is a major driver of Alzheimer's disease (AD). The role of its isoforms however remains unclear and human AD models are scarce.
methodsWe generated human MAPT- (tau-) knockout (KO) induced pluripotent stem cells (iPSC) using CRISPR/Cas9, differentiated these into glutamatergic neurons, and assessed isoform-specific functions of tau in these neurons. We used omic- approaches, live-cell imaging, subcompartmental analysis, and lentivirus-based reintroduction of specific tau isoforms to investigate isoform-mediated neuronal dysfunction in an AD model.
resultsTau KO human iPSC-derived neurons showed decreased neurite outgrowth and axon initial segment length and, notably, resisted amyloid beta oligomer (AβO)-induced neuronal activity reduction. Introducing the 1N4R-tau isoform, but not other isoforms, confers AβO vulnerability and increases KxGS phosphorylation of tau, without altering neuronal activity or microtubule modifications. DISCUSSION: While tau KO impacts neuronal development and activity, tau-KO also confers resistance against AβO insult. 1N4R-tau likely mediates AβO-induced and phosphorylated tau toxicity, representing a novel prime therapeutic target for AD. HIGHLIGHTS: Tau knockout alters neurite growth and axon initial segment formation in human neurons. Tau isoforms show differential axonal localization in human neurons. Tau depletion protects against amyloid beta oligomer (AβO)-mediated neurotoxicity. 1N4R tau mediates AβO-induced toxicity in human neurons.
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