ArticleMolecular neurobiology2020
Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death.
Article in Molecular neurobiology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.
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Who cites it
50 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Glymphatic dysfunction in Alzheimer's disease: a systematic review and meta-analysis of the DTI-ALPS index as an imaging biomarker.Frontiers in aging neuroscience · 2026Pooled it
- A Virus-Like-Particle-Based Conjugate Vaccine Targeting the Microtubule Binding Region of Tau Protein.ACS omega · 2026Article
- Mesenchymal stem cell-mediated regulation of neuroinflammation and amyloid-β clearance: A promising therapeutic strategy for Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2026Review
- Senescent cells in systemic aging: SASP heterogeneity, immune escape, and endocrine modulation.Biogerontology · 2026Review
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- FTDP-17T Mutations Promote Formation of Phosphorylated FTDP-17T TAU Oligomers That Cause Degeneration of Dopaminergic and Hippocampal Neurons via Activating ER Stress and Mitochondrial Pro-apoptotic Cascades.Neurochemical research · 2026Article
- A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.Nature communications · 2026Article
- Convolutional neural network-derived neurofibrillary tangle classifiers: Investigative tools to identify maturation levels and explore post-translational modifications using laser capture microdissection coupled mass spectrometry.Journal of neuropathology and experimental neurology · 2026Article
- Catalytic Effect of Amyloid-β on Native Tau Aggregation at Physiologically Relevant Concentrations.International journal of molecular sciences · 2025Article
- Glycogen synthase kinase-3: the master switch driving neurodegeneration in Alzheimer's disease and Parkinson's disease.Archives of toxicology · 2025Review
- Tau-Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential.Cellular and molecular neurobiology · 2025Review
- Making tau amyloid models in vitro: a crucial and underestimated challenge.FEBS letters · 2025Review
- Is the Voltage-Dependent Anion Channel a Major Player in Neurodegenerative Diseases?International journal of molecular sciences · 2025Review
- Interplay Between Aging and Tau Pathology in Alzheimer's Disease: Mechanisms and Translational Perspectives.Antioxidants (Basel, Switzerland) · 2025Review
- Hyperphosphorylated tau-based Alzheimer's Disease drug discovery: Identification of inhibitors of tau aggregation and cytotoxicity.SLAS discovery : advancing life sciences R & D · 2025Article
- Phosphorylation-Induced Self-Coacervation versus RNA-Assisted Complex Coacervation of Tau Proteins.Journal of the American Chemical Society · 2025Article
- Effects of Heparan Sulfate Trisaccharide Containing Oleanolic Acid in Attenuating Hyperphosphorylated Tau-Induced Cell Dysfunction Associated with Alzheimer's Disease.Journal of medicinal chemistry · 2025Article
- Stem cell therapy offers new hope for the treatment of Alzheimer's disease.Frontiers in cell and developmental biology · 2025Review
- Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer's disease.Open life sciences · 2025Article
- The Interplay Between Accumulation of Amyloid-Beta and Tau Proteins, PANoptosis, and Inflammation in Alzheimer's Disease.Neuromolecular medicine · 2024Review
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 2 countries.
Funding
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder without a cure or prevention to date. Hyperphosphorylated tau forms the neurofibrillary tangles (NFTs) that correlate well with the progression of cognitive impairments. Animal studies demonstrated the pathogenic role of hyperphosphorylated tau. Understanding how abnormal phosphorylation renders a normal tau prone to form toxic fibrils is key to delineating molecular pathology and to developing efficacious drugs for AD. Production of a tau bearing the disease-relevant hyperphosphorylation and molecular characters is a pivotal step. Here, we report the preparation and characterization of a recombinant hyperphosphorylated tau (p-tau) with strong relevance to disease. P-tau generated by the PIMAX approach resulted in phosphorylation at multiple epitopes linked to the progression of AD neuropathology. In stark contrast to unmodified tau that required an aggregation inducer, and which had minimal effects on cell functions, p-tau formed inducer-free fibrils that triggered a spike of mitochondrial superoxide, induced apoptosis, and caused cell death at sub-micromolar concentrations. P-tau-induced apoptosis was suppressed by inhibitors for reactive oxygen species. Hyperphosphorylation apparently caused rapid formation of a disease-related conformation. In both aggregation and cytotoxicity, p-tau exhibited seeding activities that converted the unmodified tau into a cytotoxic species with an increased propensity for fibrillization. These characters of p-tau are consistent with the emerging view that hyperphosphorylation causes tau to become an aggregation-prone and cytotoxic species that underlies diffusible pathology in AD and other tauopathies. Our results further suggest that p-tau affords a feasible tool for Alzheimer's disease mechanistic and drug discovery studies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.