Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China.
Food Chem Toxicol. 2022 Oct;168:113407. doi: 10.1016/j.fct.2022.113407. Epub 2022 Sep 6.
Glucocorticoid (GC) exposure can lead to deterioration of the structure and function of hippocampal neurons and is closely involved in Alzheimer's disease (AD). Amyloid-β (Aβ) overproduction is an important aspect of AD pathogenesis. Our study mainly investigated the mechanism of chronic GC exposure in accelerating Aβ production in primary cultured hippocampal neurons from APP/PS1 mice. The results indicated that chronic dexamethasone (DEX, 1 μM) significantly accelerated neuronal damage and Aβ accumulation in hippocampal neurons from APP/PS1 mice. Meanwhile, DEX exposure markedly upregulated APP, NCSTN, BACE1 and p-Tau/Tau expression in hippocampal neurons from APP/PS1 mice. Our study also indicated that chronic DEX exposure significantly increased intracellular Ca ([Ca]) levels and the expressions of p-PLC, CN and NFAT1 in hippocampal neurons from APP/PS1 mice. We further found that stabilizing intracellular calcium homeostasis with 2-APB (50 μM) and SKF-96365 (10 μM) significantly alleviated neuronal damage and Aβ accumulation in chronic DEX-induced hippocampal neurons from APP/PS1 mice. Additionally, dual luciferase assays showed that NFAT1 upregulated NCSTN transactivation, which was further increased upon DEX treatment. This study suggests that chronic DEX exposure accelerates Aβ accumulation by activating calcium-mediated CN-NFAT1 signaling in hippocampal neurons from APP/PS1 mice, which may be closely related to the acceleration of AD.
糖皮质激素（GC）暴露可导致海马神经元结构和功能恶化，并与阿尔茨海默病（AD）密切相关。淀粉样蛋白-β（Aβ）的过度产生是 AD 发病机制的一个重要方面。本研究主要探讨了慢性 GC 暴露加速 APP/PS1 小鼠原代海马神经元 Aβ产生的机制。结果表明，慢性地塞米松（DEX，1 μM）显著加速了 APP/PS1 小鼠海马神经元的损伤和 Aβ积累。同时，DEX 暴露明显上调了 APP、NCSTN、BACE1 和 p-Tau/Tau 在 APP/PS1 小鼠海马神经元中的表达。我们的研究还表明，慢性 DEX 暴露显著增加了 APP/PS1 小鼠海马神经元内的细胞内 Ca（[Ca]）水平和 p-PLC、CN 和 NFAT1 的表达。我们进一步发现，用 2-APB（50 μM）和 SKF-96365（10 μM）稳定细胞内钙稳态可显著减轻慢性 DEX 诱导的 APP/PS1 小鼠海马神经元的损伤和 Aβ积累。此外，双荧光素酶报告基因检测表明，NFAT1 上调了 NCSTN 的转录激活，DEX 处理后进一步增加。这项研究表明，慢性 DEX 暴露通过激活 APP/PS1 小鼠海马神经元中钙介导的 CN-NFAT1 信号通路加速 Aβ的积累，这可能与 AD 的加速密切相关。
