Activation of p38 Kinase Links Tau Phosphorylation, Oxidative Stress, and Cell Cycle-Related Events in Alzheimer Disease
Abstract
The temporal association between oxidative stress and the hallmark pathologies of Alzheimer disease (AD) demonstrates that oxidative stress is among the earliest events in the disease. Nonetheless, neither the consequences of oxidative stress nor how oxidative stress relates to other pathological features of the disease are clear at this point. To begin to address these issues, we investigated p38 kinase, which is induced by oxidative stress, in the pathogenesis of AD. In hippocampal and cortical brain regions of individuals with AD, p38 is exclusively localized in association with neurofibrillar pathology. By marked contrast, these brain regions exhibit a low level of diffuse p38 staining in the neuronal cytoplasm in controls. We found a complete overlap of the immunostaining profiles of p38 and tau-positive neurofibrillary pathology and that the majority of p38 was activated in AD neurons, both of which support an association of p38 with the disease process. Moreover, the finding that PHF-tau co-immunoprecipitates with p38, and that p38 co-purifies with PHF-tau, strongly suggests that they are physically associated in vivo. Since p38 is also implicated in cell cycle regulation, our findings provide a link between the cell cycle re-entrant phenotype, cytoskeletal phosphorylation and oxidative stress in AD.
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Phospho-p38 is found exclusively in cells with NFT or tau aggregates in AD cases, co-localizes with tau aggregates in tauopathic brains, and co-precipitates with insoluble tau in both human cases and transgenic AD mouse models.
“Phospho-p38 is found exclusively in cells with NFT or tau aggregates in AD cases (152,153), co-localizes with tau aggregates in tauopathic brains (145,154) and co-precipitates with insoluble tau in both human cases and transgenic AD mouse models (145,148).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [152]
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- Authors
- Zhu, X., Rottkamp, C. A., Boux, H., Takeda, A., Perry, G., & Smith, M. A.
- Affiliations
- Case Western Reserve University (US)
- Tohoku University (JP)
- Corresponding author
- Smith, Mark A.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-10
- Volume
- 59
- Issue
- 10
- Pages
- 880-888
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W2288430548
- Cited by
- 378
- References
- 3
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 17 · 2023: 11 · 2022: 6 · 2021: 16 · 2020: 16 · 2019: 10 · 2018: 18 · 2017: 13 · 2016: 7 · 2015: 8 · 2014: 6 · 2013: 10 · 2012: 15
- FWCI
- 13.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (5r01ag009287-08)
- National Institute on Aging (AG 09287)
- National Institute of Neurological Disorders and Stroke (NS 38648, R01NS038648)
- 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
- p38 MAPK, tau phosphorylation, oxidative stress, Alzheimer's disease, neurofibrillary tangles, PHF-tau, cell cycle re-entry, hippocampus, cortex
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cell Division, Enzyme Activation, Humans, Middle Aged, Neurons, Phosphorylation, tau Proteins, Apoptosis, Oxidative Stress, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases
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