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The Importance of Tau Phosphorylation for Neurodegenerative Diseases
Open accessAbstract
Fibrillar deposits of highly phosphorylated tau are a key pathological feature of several neurodegenerative tauopathies including Alzheimer's disease (AD) and some frontotemporal dementias. Increasing evidence suggests that the presence of these end-stage neurofibrillary lesions do not cause neuronal loss, but rather that alterations to soluble tau proteins induce neurodegeneration. In particular, aberrant tau phosphorylation is acknowledged to be a key disease process, influencing tau structure, distribution, and function in neurons. Although typically described as a cytosolic protein that associates with microtubules and regulates axonal transport, several additional functions of tau have recently been demonstrated, including roles in DNA stabilization, and synaptic function. Most recently, studies examining the trans-synaptic spread of tau pathology in disease models have suggested a potential role for extracellular tau in cell signaling pathways intrinsic to neurodegeneration. Here we review the evidence showing that tau phosphorylation plays a key role in neurodegenerative tauopathies. We also comment on the tractability of altering phosphorylation-dependent tau functions for therapeutic intervention in AD and related disorders.
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“Tau has been shown to be associated with synaptic dysfunction, and while tau is normally associated with and stabilizes microtubules, tau phosphorylation results in dissociation from microtubules, tau redistribution to somatodendritic compartments and synaptic dysfunction (Hoover, Reed et al. 2010, Noble, Hanger et al. 2013, Spires-Jones and Hyman 2014).”
From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Noble, Hanger et al. 2013
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“Because tau phosphorylation is likely to promote axonal degeneration and eventual neuronal death, we analyzed cell death within the brains of our 5xFAD models.”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Noble et al., 2013
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“A marker of progressive AD in both humans and mice is the hyperphosphorylation of the microtubule-stabilizing protein tau. The incidence of tau phosphorylation increases as disease progresses and leads to microtubule de-stabilization and failure of the microtubule architecture, especially within neuronal axons (Frost et al., 2015; Gong and Iqbal, 2008; Noble et al., 2013).”
From LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease (2019) · cites this paper as Noble et al., 2013
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Metadata
- Authors
- Noble, W., Hanger, D. P., Miller, C. C. J., & Lovestone, S.
- Affiliations
- King's College London (GB)
- Corresponding author
- Noble, Wendy
- Lovestone, Simon
- Venue
- Frontiers in Neurology
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 4
- Pages
- 83-83
- ISSN
- 1664-2295 (ISSN-L)
- PMC
- PMC3696910
- OpenAlex
- W2011634611
- Cited by
- 475
- References
- 169
- Citations by year
- 2026: 27 · 2025: 51 · 2024: 56 · 2023: 58 · 2022: 56 · 2021: 56 · 2020: 35 · 2019: 24 · 2018: 28 · 2017: 26 · 2016: 17 · 2015: 19 · 2014: 17 · 2013: 4
- FWCI
- 13.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0512-10053)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K500343/1)
- Directorate for Biological Sciences
- Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- tau phosphorylation, tauopathy, Alzheimer's disease, frontotemporal dementia, neurofibrillary tangles, soluble tau, trans-synaptic spread, extracellular tau, synaptic function, DNA stabilization, axonal transport, neurodegeneration, therapeutic target
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