Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity
Abstract
Accumulation of abnormally hyperphosphorylated tau (P-tau) in the form of tangles of paired helical filaments and/or straight filaments is one of the hallmarks of Alzheimer's disease (AD) and other tauopathies. P-tau is also found unpolymerized in AD. Although the cognitive decline is known to correlate with the degree of neurofibrillary pathology, whether the formation of filaments or the preceding abnormal hyperphosphorylation of tau is the inhibitory entity that leads to neurodegeneration has been elusive. We have previously shown that cytosolic abnormaly hyperphosphorylated tau in AD brain (AD P-tau) sequesters normal tau (N-tau), microtubule-associated protein (MAP) 1, and MAP2, which results in the inhibition of microtubule assembly and disruption of microtubules. Here, we show that polymerization of AD P-tau into filaments inhibits its ability to bind N-tau and as well as the ability to inhibit the assembly of tubulin into microtubules in vitro and in the regenerating microtubule system from cultured cells. Like AD P-tau, the in vitro abnormally hyperphosphorylated recombinant brain N-tau binds N-tau and loses this binding activity on polymerization into filaments. Dissociation of the hyperphosphorylated N-tau filaments by ultrasonication restores its ability to bind N-tau. These findings suggest that the nonfibrillized P-tau is most likely the responsible entity for the disruption of microtubules in neurons in AD. The efforts in finding a therapeutic intervention for tau-induced neurodegeneration need to be directed either to prevent the abnormal hyperphosphorylation of this protein or to neutralize its binding to normal MAPs, rather than to prevent its aggregation into filaments.
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Tau-mediated neurodegeneration arises from multiple pathological mechanisms including loss of normal function, gain of toxic function, aggregation, and mislocalization.
“Tau-mediated neurodegeneration arises from multiple pathological mechanisms, including loss of normal function [37–42], gain of toxic function [43–46], aggregation [44, 47–49], and mislocalization [50–52].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [45]
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Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease
Chimal-Juárez, E., Patel, H., Jury-Garfe, N., Dabin, L. C., Vidal, R., Kim, J., & Lasagna-Reeves, C. A. (2026) · bioRxiv · doi:10.64898/2026.05.12.724684
- Authors
- Alonso, A. D. C., Li, B., Grundke-Iqbal, I., & Iqbal, K.
- Affiliations
- New York State Office for People With Developmental Disabilities (US)
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399
- ORCID
- Iqbal, Khalid
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-06-06
- Volume
- 103
- Issue
- 23
- Pages
- 8864-8869
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2126124658
- Cited by
- 206
- References
- 4
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 10 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 6 · 2019: 8 · 2018: 11 · 2017: 5 · 2016: 11 · 2015: 8 · 2014: 8 · 2013: 16 · 2012: 9
- FWCI
- 11.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG19158, R01AG019158)
- National Institute of Neurological Disorders and Stroke (NS/NS31862)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- hyperphosphorylated tau, paired helical filaments, Alzheimer's disease, tauopathy, microtubule assembly inhibition, microtubule disruption, MAP1, MAP2, neurofibrillary tangles
- MeSH terms
- Alzheimer Disease, Animals, Biopolymers, Cells, Cultured, Humans, Microtubules, Models, Biological, Neurofibrils, Phosphorylation, Protein Binding, 3T3 Cells, tau Proteins, Protein Structure, Quaternary, Mice
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