Dysregulation of tau phosphorylation in mouse brain during excitotoxic damage.
Open accessAbstract
Glutamate receptor-mediated excitotoxicity is thought to contribute to the development of Alzheimer's disease (AD), but the underlying mechanism is unknown. In this study, we investigated the dynamic changes of tau phosphorylation and tau-related protein kinases and protein phosphatase 2A (PP2A) in the mouse brain during excitotoxicity induced by intraperitoneal injection of 20 mg/kg kainic acid (KA). We found that KA-induced excitotoxicity led to transient dephosphorylation of tau (within 6 hr post-injection), followed by sustained hyperphosphorylation of tau at multiple sites that are hyperphosphorylated in AD brain. The initial dephosphorylation of tau may result from activation of PP2A, and the sustained hyperphosphorylation may be due mainly to activation of cdk5 and down-regulation of PP2A during the later phase. Because abnormal hyperphosphorylation of tau plays a crucial role in neurodegeneration and in the formation of neurofibrillary tangles, our results suggest that glutamate receptor-mediated excitotoxicity might contribute to AD partially via promoting abnormal hyperphosphorylation of tau in AD brain.
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Following kainic acid administration in mice, biphasic changes in p-tau levels occur, with decreased phosphorylation within the first 6-h period followed by a gradual 3-5-fold increase until a 48-h endpoint.
“Following kainic acid administration in mice, biphasic changes in p-tau levels occur, where decreased phosphorylation is first observed within the first 6-h period followed by a gradual 3–5-fold increase until a 48-h endpoint.”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liang et al., 2009
The Results section reports decreased tau phosphorylation within 6 hours of kainic acid injection, followed by increases reaching 3–4-fold at some sites and more than 5-fold at others. It does not support a gradual, uniform increase through 48 hours: phosphorylation rose quickly after 6 hours, remained elevated through 48 hours at one group of sites, and later declined at another. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSustained increases in p-tau levels following kainic acid administration are accompanied by only transient increases in GSK-3β activity.
“However, the observation of sustained increases in p-tau levels following kainic acid administration being accompanied by only transient increases in GSK-3β activity (Liang et al., 2009) and the lack of effect on hippocampal p-tau by GSK-3β inhibitor pretreatment in the intra-amygdala kainic acid-induced status epilepticus mouse model (Alves et al., 2019) indicate that GSK-3β is not the only”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liang et al., 2009
Progressive activation of CDK5 co-occurs with increasing tau phosphorylation in rodent seizure models.
“Furthermore, progressive activation of CDK5 co-occurs with increasing tau phosphorylation in rodent seizure models (Chen et al., 2000; Liang et al., 2009), indicating significant mediation of seizure-associated tau hyperphosphorylation by CDK5.”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liang et al., 2009
The biphasic p-tau progression after kainic acid is accompanied by a corresponding increase and then decrease in activation of protein phosphatase 2A.
“This progression is accompanied by a corresponding increase and then decrease in the activation of protein phosphatase 2A (PP2A) (Liang et al., 2009), which is estimated to account for 70% of human brain tau dephosphorylation (Wang and Mandelkow, 2016).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Liang et al., 2009
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- [3]Iqbal K Alonso A del C Chohan MO El-Akkad E Gong C Khatoon S Liu F Grundke-Iqbal I Dawbarn D Allen SJ 2007 Molecular basis of tau protein pathology: role of abnormal hyperphosphorylation Neurobiology of Alzheimer’s Disease Oxford University Press New York 111 131
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- Authors
- Liang, Z., Liu, F., Iqbal, K., Grundke-Iqbal, I., & Gong, C.-X.
- Affiliations
- Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
- Corresponding author
- Gong, Cheng-Xin
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2009-07-01
- Volume
- 17
- Issue
- 3
- Pages
- 531-539
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC2829309
- OpenAlex
- W298745165
- Cited by
- 73
- References
- 55
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 11 · 2019: 5 · 2018: 5 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 4
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG 019158, R01AG019158, AG027429, R01AG027429)
- 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 phosphorylation, excitotoxicity
- MeSH terms
- Animals, Brain Injuries, Gene Expression Regulation, Kainic Acid, Male, Phosphorylation, Time Factors, tau Proteins, Excitatory Amino Acid Agonists, Protein Subunits, Glycogen Synthase Kinase 3, Immunoprecipitation, Mice, Protein Phosphatase 2
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