Chronic glucocorticoid exposure accelerates Aβ generation and neurotoxicity by activating calcium-mediated CN-NFAT1 signaling in hippocampal neurons in APP/PS1 mice

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-beta (A beta) overproduction is an important aspect of AD pathogenesis. Our study mainly investigated the mechanism of chronic GC exposure in accelerating A beta pro-duction in primary cultured hippocampal neurons from APP/PS1 mice. The results indicated that chronic dexamethasone (DEX, 1 mu M) significantly accelerated neuronal damage and A beta 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 Ca2+ ([Ca2+]i) levels and the expressions of p-PLC, CN and NFAT1 in hip-pocampal neurons from APP/PS1 mice. We further found that stabilizing intracellular calcium homeostasis with 2-APB (50 mu M) and SKF-96365 (10 mu M) significantly alleviated neuronal damage and A beta 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 A beta 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.