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.
Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China.
Mol Neurobiol. 2022 Jul;59(7):4488-4500. doi: 10.1007/s12035-022-02850-2. Epub 2022 May 16.
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-β 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.
阿尔茨海默病（AD）的病理学特征包括由淀粉样β（Aβ）沉积引起的老年斑形成和由tau 过度磷酸化引起的神经原纤维缠结。减少 tau 过度磷酸化对于 AD 的治疗至关重要。网络药理学分析表明，丹参酮（CTS）可能通过调节磷酸肌醇 3 激酶/蛋白激酶 B/糖原合酶激酶 3β（PI3K/Akt/GSK3β）通路来降低 tau 过度磷酸化。我们研究了隐丹参酮（CTS）降低 Aβ诱导的 tau 过度磷酸化的能力，并探讨了其潜在机制。采用淀粉样β寡聚物（AβO）建立 HT22 细胞 AD 模型。用 Western blot 和免疫荧光染色法测定 PI3K/Akt/GSK3β 通路中 tau 及其相关蛋白的表达水平。然后在 OKA 诱导的 AD 细胞模型中评价上述蛋白，以验证结果。还评估了突触相关蛋白包括突触后密度蛋白-95（PSD95）和突触小体蛋白。结果发现，CTS 可显著降低 AβO 和 OKA 诱导的细胞模型中 tau 在 Ser202、Ser404、Thr181 和 Thr231 处的过度磷酸化。此外，还发现 CTS 逆转了 AβO 诱导的 PSD95 和突触小体蛋白水平降低。用 LY294002 阻断 PI3K，结果表明 CTS 通过调节 PI3K/Akt/GSK3β 信号通路发挥神经保护作用。综上所述，首次表明 CTS 通过 PI3K/Akt/GSK3β 通路抑制 AD 相关 tau 过度磷酸化，并降低 AβO 对 HT22 细胞中 PSD95 和突触小体蛋白表达水平的影响。
