Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau
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The microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer disease and accumulates in neurons undergoing neurofibrillary degeneration. In the present study, the associations of the Alzheimer-hyperphosphorylated tau (AD P-tau) with the high molecular weight MAPs (HMW-MAPs) MAP1 and MAP2 were investigated. The AD P-tau was found to aggregate with MAP1 and MAP2 in solution. The association of AD P-tau to the MAPs resulted in inhibition of MAP-promoted microtubule assembly. However, unlike the coaggregation of AD P-tau and normal tau, the association between AD P-tau and the HMW-MAPs did not result in the formation of filaments/tangles. The affinity of the tau-AD P-tau association was higher than that of HMW-MAPs-AD P-tau because normal tau inhibited the latter binding. The association between AD P-tau and the HMW-MAPs also appeared to occur in situ because these proteins cosedimented from the Alzheimer brain extracts, and, in the sediment, the levels of the HMW-MAPs correlated with the levels of AD P-tau. These studies suggested that the abnormally phosphorylated tau can sequester both normal tau and HMW-MAPs and disassemble microtubules but, under physiological conditions, can form tangles of filaments only from tau.
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MAP2 was found sequestered in a sedimentable fraction from AD brain homogenate containing small tau aggregates/oligomers referred to as AD P-tau.
“Furthermore, MAP2 was found sequestered in a sedimentable fraction from AD brain homogenate containing small tau aggregates/oligomers referred to as AD P-tau (37).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [37]
In this sequestered form, MAP2 lost its ability to facilitate microtubule assembly.
“Markedly, in this sequestered form, MAP2 lost its ability to facilitate microtubule assembly (37).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [37]
The sequestering of MAP2 compromises microtubule stability.
“Whereas the sequestering of MAP2 compromises microtubule stability (37)”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [37]
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- Authors
- Alonso, A. D. C., Grundke-Iqbal, I., Barra, H. S., & Iqbal, K.
- Affiliations
- Research Centre in Biological Chemistry of Córdoba (AR)
- Departmento de Química Biológica, Facultad de Ciencias Químicas, Centro de Investigaciones en Química Biológica de Córdoba, C.C.61, 5000-Córdoba, Argentina; and New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314
- ORCID
- Iqbal, Khalid
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-01-07
- Volume
- 94
- Issue
- 1
- Pages
- 298-303
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC19321
- OpenAlex
- W1985053970
- Cited by
- 437
- References
- 1
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 16 · 2023: 17 · 2022: 20 · 2021: 21 · 2020: 15 · 2019: 16 · 2018: 15 · 2017: 20 · 2016: 7 · 2015: 9 · 2014: 20 · 2013: 27 · 2012: 19
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag008076-09, 5r01ag005892-16, 5r03tw000507-06)
- National Institute on Aging (AG-05892, AG 08076)
- Fogarty International Center (TW 00507)
- 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
- tau hyperphosphorylation, Alzheimer's disease, neurofibrillary degeneration, microtubule-associated proteins, MAP1, MAP2, microtubule disassembly, microtubule assembly inhibition, protein aggregation, tau tangles, protein-protein binding
- MeSH terms
- Alzheimer Disease, Binding, Competitive, Humans, Microtubule-Associated Proteins, Microtubules, Phosphorylation, Protein Binding, tau Proteins
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