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Forskolin Induces Hyperphosphorylation of Tau Accompanied by Cell Cycle Reactivation in Primary Hippocampal Neurons

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An Erratum to this article was published on 07 February 2017

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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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  • 07 February 2017

    An erratum to this article has been published.

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Acknowledgments

This work is supported in part by grants from the National Natural Science Foundation of China (81572222 and 30900725) and Guangdong Provincial Natural Science Foundation (2014A030313333 and 8151051501000005).

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Authors and Affiliations

  1. Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Hai-Hong Wang, Yan Li, Ang Li, Fang Yan, Zhen-Lin Li, Zhong-Ying Liu, Lei Zhang, Wei-Ren Dong & Lin Zhang

  2. Department of Oncology, Zhujiang Hospital of Southern Medical University, Guangzhou, 510280, China

    Jian Zhang

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  1. Hai-Hong Wang
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Correspondence to Wei-Ren Dong or Lin Zhang.

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This study using primary cell culture met all institution and national standards for experimental ethics.

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The authors declare that they have no conflict of interest.

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An erratum to this article is available at https://doi.org/10.1007/s12035-017-0415-8.

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Wang, HH., Li, Y., Li, A. et al. Forskolin Induces Hyperphosphorylation of Tau Accompanied by Cell Cycle Reactivation in Primary Hippocampal Neurons. Mol Neurobiol 55, 696–706 (2018). https://doi.org/10.1007/s12035-016-0348-7

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