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Cryptotanshinone Attenuates Amyloid-β42-induced Tau Phosphorylation by Regulating PI3K/Akt/GSK3β Pathway in HT22 Cells

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Abstract

The pathological characteristics of Alzheimer’s disease (AD) include formation of senile plaques resulting from amyloid-β (Aβ) deposition and neurofibrillary tangles caused by tau hyperphosphorylation. Reducing tau hyperphosphorylation is crucial for treatment of AD. Network pharmacology analysis showed that CTS may reduce tau hyperphosphorylation by regulating the phosphatidylinositol 3 kinases/protein kinase B/ glycogen synthase kinase-3β (PI3K/Akt/GSK3β) pathway. We investigated the ability of cryptotanshinone (CTS) to reduce Aβ-induced tau hyperphosphorylation and characterized the underlying mechanisms. Amyloid-β42 oligomers (AβO) were used to establish an AD model in HT22 cells. The expression levels of tau and related proteins in PI3K/Akt/GSK3β pathway were measured using western blot and immunofluorescence staining. The above-mentioned proteins were then evaluated in an okadaic acid (OKA)-induced AD cell model to verify the results. Synapse-associated proteins including post-synaptic density protein-95 (PSD95) and synaptophysin were also evaluated. We found that CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231 in AβO- and OKA-induced cell models. Moreover, we also found that CTS reversed AβO-induced reductions in the levels of PSD95 and synaptophysin. We used LY294002 to block PI3K and the results showed that CTS exerted neuroprotective effects through regulation of the PI3K/Akt/GSK3β signaling pathway. In summary, we showed for the first time that CTS inhibited AD-related tau hyperphosphorylation and reduced the effects of AβO on the expression levels of PSD95 and synaptophysin via the PI3K/Akt/GSK3β pathway in HT22 cells.

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Data Availability

The datasets generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We wish to thank Dr. Heng Zhang, Dr. Yan Li, Dr. Yuqing Shi for their selfless help on performing experiments and suggestions on revising the manuscript. We wish to thank Yana Pang and Bingqiu Li for their guidance.

Funding

This study was supported by the Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital. This study was supported by the Key Project of the National Natural Science Foundation of China (81530036), the National Key Scientific Instrument and Equipment Development Project (31627803), Beijing Scholars Program, Beijing Brain Initiative from Beijing Municipal Science and Technology Commission (Z2011000 05520016 and Z201100005520017), and the Key Project of the National Natural Science Foundation of China (U20A20354).

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Authors and Affiliations

  1. Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, National Clinical Research Center for Geriatric Diseases, Capital Medical University, 45 Changchun Street, Beijing, China

    Diyang Lyu & Jianping Jia

  2. Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China

    Jianping Jia

  3. Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, China

    Jianping Jia

  4. Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China

    Jianping Jia

  5. Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China

    Jianping Jia

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  1. Diyang Lyu
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  2. Jianping Jia
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JJ contributed to the research concept and the study design. DL designed the study, performed experiments, analyzed data, drawn figures, and wrote the manuscript. JJ revised the manuscript critically and obtained funding. All authors contributed to the article and approved the submitted manuscript.

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Correspondence to Jianping Jia.

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Lyu, D., Jia, J. Cryptotanshinone Attenuates Amyloid-β42-induced Tau Phosphorylation by Regulating PI3K/Akt/GSK3β Pathway in HT22 Cells. Mol Neurobiol 59, 4488–4500 (2022). https://doi.org/10.1007/s12035-022-02850-2

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