2. Academic Validation
  3. Cryptotanshinone Attenuates Amyloid-β42-induced Tau Phosphorylation by Regulating PI3K/Akt/GSK3β Pathway in HT22 Cells

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

  • Mol Neurobiol. 2022 Jul;59(7):4488-4500. doi: 10.1007/s12035-022-02850-2.
Diyang Lyu 1,  Jianping Jia 2 3 4 5 6
Affiliations

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.
  • 2 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. [email protected].
  • 3 Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China. [email protected].
  • 4 Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, China. [email protected].
  • 5 Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China. [email protected].
  • 6 Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China. [email protected].
PMID: 35575872 DOI: 10.1007/s12035-022-02850-2
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.

Keywords

Alzheimer’s disease; Cryptotanshinone; Neuronal protection; Okadaic acid; Tau phosphorylation.

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