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Cited by 477Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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The Importance of Tau Phosphorylation for Neurodegenerative Diseases

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Noble, Wendy, Hanger, Diane P., Miller, Christopher C. J., Lovestone, Simon·2013·Frontiers in Neurology
DOI 10.3389/fneur.2013.00083PMC PMC3696910
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Abstract

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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Figures

Figure 1 The human tau gene and six protein isoforms. (A) The six isoforms of human CNS tau. Exons 2 and 3 (E2 and E3) encode two different inserts of 28 amino acids near the N-terminus of tau. Absence of E2 and E3 gives rise to 0N tau isoforms, whereas inclusion of E2 produces 1N and inclusion of both E2 and E3 results in 2N tau isoforms. M1–M4 represent the four imperfect-repeat microtubule-binding domains, M2 being encoded by exon 10. Lack of M2 results in the formation of 3R tau and M2 inclusion results in 4R tau isoforms. The proline-rich domain in the center of the tau polypeptide is indicated. Alternative-splicing produces tau isoforms of 352–441 amino acids, as indicated. (B) Positioning of phosphorylation sites on tau from Alzheimer brain. Approximately 45 phosphorylation sites have been identified, these are found predominantly in the proline-rich domain and the regions flanking the microtubule-binding domain.
Figure 1 The human tau gene and six protein isoforms. (A) The six isoforms of human CNS tau. Exons 2 and 3 (E2 and E3) encode two different inserts of 28 amino acids near the N-terminus of tau. Absence of E2 and E3 gives rise to 0N tau isoforms, whereas inclusion of E2 produces 1N and inclusion of both E2 and E3 results in 2N tau isoforms. M1–M4 represent the four imperfect-repeat microtubule-binding domains, M2 being encoded by exon 10. Lack of M2 results in the formation of 3R tau and M2 inclusion results in 4R tau isoforms. The proline-rich domain in the center of the tau polypeptide is indicated. Alternative-splicing produces tau isoforms of 352–441 amino acids, as indicated. (B) Positioning of phosphorylation sites on tau from Alzheimer brain. Approximately 45 phosphorylation sites have been identified, these are found predominantly in the proline-rich domain and the regions flanking the microtubule-binding domain.CC BY · PubMed Central
Figure 2 The impact of phosphorylation on tau functions in different cell locations. The figure shows the functions of tau in different cellular compartments that are influenced by tau phosphorylation, and that likely contribute to the development or progression of neurodegenerative tauopathies.
Figure 2 The impact of phosphorylation on tau functions in different cell locations. The figure shows the functions of tau in different cellular compartments that are influenced by tau phosphorylation, and that likely contribute to the development or progression of neurodegenerative tauopathies.CC BY · PubMed Central

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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
ORCID
Venue
Frontiers in Neurology
Publisher
Frontiers Media SA
Published
2013
Volume
4
Pages
83-83
ISSN
1664-2295 (ISSN-L)
DOI
10.3389/fneur.2013.00083
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
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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