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Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats
Abstract
Tau hyperphosphorylation leads to formation of paired helical filament/neurofibrillary tangles, the hallmark lesion seen in Alzheimer's disease (AD) brain. An imbalanced regulation in protein kinases and protein phosphatases in the affected neurons is proposed to be a reasonable causative factor to the disease process. To verify the hypothesis, we have injected in the present study calyculin A, a potent and specific inhibitor of protein phosphatase (PP) 2A and PP1, into rat hippocampus bilaterally, thus reproduced an Alzheimer's-like deficiency in dephosphorylation system. It was found that calyculin A-injected rats developed lesions in spatial memory retention in Morris water maze test. At mean time, tau was hyperphosphorylated at Ser396/Ser404 (PHF-1) and Ser-262/Ser-356 (12E8) sites determined both by immunohistochemistry and Western blot. It is implicated that (1) PP2A and PP1 participate in the in vivo regulation of tau phosphorylation, and down-regulation of the two phosphatases will result in tau hyperphosphorylation; (2) hyperphosphorylation of tau at PHF-1 and 12E8 sites might be crucial to affect spatial memory in AD.
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“Inhibition of PP2A in cultured brain slices and rat brains induced tau hyperphosphorylation at multiple sites known to be related to AD (Gong et al., 2000; Sun et al., 2003).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Sun et al., 2003
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Metadata
- Authors
- Sun, L., Liu, S. Y., Zhou, X. W., Wang, X. C., Liu, R., Wang, Q., & Wang, J. Z.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Corresponding author
- Wang, J.Z
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 118
- Issue
- 4
- Pages
- 1175-1182
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2040147265
- Cited by
- 168
- References
- 56
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 4 · 2020: 8 · 2019: 4 · 2018: 9 · 2017: 5 · 2016: 5 · 2015: 6 · 2014: 8 · 2013: 6 · 2012: 9
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- 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
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- tau hyperphosphorylation, protein phosphatase 2A, protein phosphatase 1, calyculin A, Alzheimer's disease, spatial memory, hippocampus, neurofibrillary tangles, paired helical filaments, PHF1, protein dephosphorylation, Morris water maze
- MeSH terms
- Animals, Antibodies, Avoidance Learning, Behavior, Animal, Enzyme Inhibitors, Hippocampus, Immunohistochemistry, Male, Marine Toxins, Oxazoles, Phosphoprotein Phosphatases, Phosphorylation, Spatial Behavior, Swimming, Time Factors, Blotting, Western, tau Proteins, Rats, Sprague-Dawley, Rats, Protein Phosphatase 1, Protein Phosphatase 2
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