The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration
Open accessAbstract
Microtubule associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and related tauopathies; in this form it is the major protein subunit of paired helical filaments (PHF)/neurofibrillary tangles. However, the nature of protein kinases and phosphatases and tau sites involved in this lesion has been elusive. We investigated self‐assembly and microtubule assembly promoting activities of hyperphosphorylated tau isolated from Alzheimer disease brain cytosol, the AD abnormally hyperphosphorylated tau (AD P‐tau) before and after dephosphorylation by phosphoseryl/phosphothreonyl protein phosphatase‐2A (PP‐2A), and then rephosphorylation by cyclic AMP‐dependent protein kinase (PKA), calcium, calmodulin‐dependent protein kinase II (CaMKII), glycogen synthase kinase‐3β (GSK‐3β) and cyclin‐dependent protein kinase 5 (cdk5) in different kinase combinations. We found that (i) dephosphorylation of AD P‐tau by PP‐2A inhibits its polymerization into PHF/straight filaments (SF) and restores its binding and ability to promote assembly of tubulin into microtubules; (ii) rephosphorylation of PP‐2A‐dephosphorylated AD P‐tau by sequential phosphorylation by PKA, CaMKII and GSK‐3β or cdk5, and as well as by cdk5 and GSK‐3β, promotes its self‐assembly into tangles of PHF similar to those seen in Alzheimer brain, and (iii) phosphorylation of tau sites required for this pathology are Thr231 and Ser262, along with several sites flanking the microtubule binding repeat region. Phosphorylation of recombinant human brain tau 441 yielded similar results as the PP‐2A dephosphorylated AD P‐tau, except that mostly SF were formed. The conditions for the abnormal hyperphosphorylation of tau that promoted its self‐assembly also induced the microtubule assembly inhibitory activity. These findings suggest that activation of PP‐2A or inhibition of either both GSK‐3β and cdk5 or one of these two kinases plus PKA or CaMKII might be required to inhibit Alzheimer neurofibrillary degeneration.
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Self-citationA protein factor essential for microtubule assembly
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Microtubule-associated protein tau. A component of Alzheimer paired helical filaments.
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Self-citationTau pathology in Alzheimer disease and other tauopathies
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Phosphorylation affects the ability of tau protein to promote microtubule assembly.
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Self-citationRole of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease.
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Self-citationDEFECTIVE BRAIN MICROTUBULE ASSEMBLY IN ALZHEIMER'S DISEASE
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Self-citationPhosphoprotein Phosphatase Activities in Alzheimer Disease Brain
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Multi-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003
Classification and basic pathology of Alzheimer disease
Duyckaerts, C., Delatour, B., & Potier, M.-C. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0532-1 · Cited by 1,031
Saman, S., Kim, W., Raya, M., Visnick, Y., Miro, S., Saman, S., Jackson, B., McKee, A. C., Alvarez, V. E., Lee, N. C. Y., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.277061 · Cited by 985
Tau and neurodegenerative disease: the story so far
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Metadata
- Authors
- Wang, J., Grundke‐Iqbal, I., & Iqbal, K.
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2007-01
- Volume
- 25
- Issue
- 1
- Pages
- 59-68
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W1954244449
- Cited by
- 553
- References
- 51
- FWCI
- 23.53
- Type
- journal article
- Language
- en
- Open access
- green
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