Forskolin Induces Hyperphosphorylation of Tau Accompanied by Cell Cycle Reactivation in Primary Hippocampal Neurons
Abstract
Abnormally hyperphosphorylated tau is the major protein constituent of neurofibrillary tangles (NFTs) in the brain of Alzheimer disease (AD) patients. Cell cycle reactivation is considered an important neuropathological feature of AD, and re-expression and activation of cell cycle regulators are known to occur in neurons containing NFTs. The aim of the present study was to investigate cell cycle reactivation during tau hyperphosphorylation in primary hippocampal neurons. We used forskolin, a specific activator of PKA, to induce tau hyperphosphorylation in cultured primary hippocampal neurons, and then measured levels of cyclin D1 and cyclin B1. We found that forskolin induced hyperphosphorylation of tau at Ser214, Ser396, and Ser202/Thr205 sites, attaining peak levels at 6, 12, and 12 h, respectively, while returning to normal levels at 24 h. Forskolin also induced a sustained cAMP elevation and PKA activation, which peaked at 6 h, in association with activation and overexpression of protein phosphatase-2A (PP-2A) at 24 h. The tau hyperphosphorylation was accompanied by increases in cyclin D1 and cyclin B1 levels; immunostaining showed overlapping distribution of hyperphosphorylated tau and cyclin D1 and cyclin B1 in primary hippocampal neurons. Forskolin induced hyperphosphorylation of tau and increased cyclin D1 and cyclin B1 protein levels in HEK293/tau441 cells, but not in the HEK293/vector cells, whereas the PKA inhibitor H89 inhibited the effects of forskolin on tau hyperphosphorylation and cyclin D1 and cyclin B1 protein levels. These findings suggest that forskolin induces tau hyperphosphorylation, which is itself necessary for the subsequent increases of cyclin D1 and cyclin B1 levels.
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The PKA-specific activator forskolin induces hyperphosphorylation of tau protein at Ser214, Ser396, and Ser202/Thr205 sites in cultured primary hippocampal neurons.
“The PKA-specific activator forskolin induces the hyperphosphorylation of tau protein at the Ser214, Ser396, and Ser202/Thr205 sites in cultured primary hippocampal neurons [154].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [154]
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- Authors
- Wang, H.-H., Li, Y., Li, A., Yan, F., Li, Z.-L., Liu, Z.-Y., Zhang, L., Zhang, J., Dong, W.-R., & Zhang, L.
- Affiliations
- Southern Medical University (CN)
- Zhujiang Hospital (CN)
- Corresponding author
- Dong, Wei-Ren
- Zhang, Lin
- Venue
- Molecular Neurobiology
- Published
- 2016-12-19
- Volume
- 55
- Issue
- 1
- Pages
- 696-706
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- OpenAlex
- W2564459072
- Cited by
- 19
- References
- 38
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-02-07)
- Open access
- closed
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Nationa Natural Science Foundation of China (81572222)
- National Natural Science Foundation of China (30900725)
- Guangdong Provincial Natural Science Foundation (2014A030313333, 8151051501000005)
- 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, forskolin, cell cycle re-entry, hippocampal neurons, cyclin D1, cyclin B1, protein kinase A, cAMP signaling, protein phosphatase 2A, Alzheimer's disease, neurofibrillary tangles, H89
- MeSH terms
- Cyclic AMP, Animals, Animals, Newborn, Cell Cycle, Cells, Cultured, Colforsin, Hippocampus, Humans, Isoquinolines, Neurons, Phosphorylation, Sulfonamides, tau Proteins, Rats, Sprague-Dawley, Cyclic AMP-Dependent Protein Kinases, Cyclin D1, Protein Phosphatase 2, Cyclin B1, HEK293 Cells
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