SOCE-mediated NFAT1-NOX2-NLRP1 inflammasome involves in lipopolysaccharide-induced neuronal damage and A beta generation

The level of lipopolysaccharide (LPS) is higher in the blood and brains of patients with Alzheimer's disease (AD), and this phenomenon is strongly linked to AD-related neuronal damage and beta-amyloid (A beta) generation. However, the mechanism by which LPS causes neuronal damage has still not been fully clarified. Oxidative stress, neuroinflammation, and Ca2+ overload are regarded as important factors influencing AD. NADPH oxidase 2 (NOX2) and the NOD-like receptor family protein 1 (NLRP1) inflammasome play important roles in promoting oxidative stress and inflammation in neurons. Ca2+ overload can activate calcineurin (CN), which further dephosphorylates nuclear factor of activated T cells (NFAT), leading to its translocation into the nucleus to regulate gene transcription. In the present study, LPS (250 mu g/kg) exposure for 14 days was used to induce cognitive dysfunction in mice and LPS (20 mu g/ml) exposure for 48 h was used to induce neuronal damage in HT22 cells. The results showed that LPS exposure activated phospholipase C (PLC), CN, and NFAT1; increased the expressions of NOX2- and NLRP1-related proteins; and promoted neuronal damage and A beta deposition in mice and HT22 cells. However, treatment with 2-APB (SOCE inhibitor), apocynin (NOX inhibitor), or tempol (reactive oxygen species scavenger) significantly reversed these LPS-induced changes, and improved neuronal damage and A beta deposition. Moreover, LPS exposure promoted PLC phosphorylation, increased the level of inositol-1,4,5-triphosphate, elevated the intracellular Ca2+ concentration ([Ca2+](i)), and disrupted [Ca2+](i) homeostasis in HT22 cells. These data indicated that the activation of SOCE-mediated NFAT1-NOX2-NLRP1 inflammasome involves in LPS-induced neuronal damage and A beta generation.

Automated summary

The presence of lipopolysaccharide (LPS) is associated with higher levels of LPS in the blood and brains of Alzheimer's disease (AD) patients, which is linked to neuronal damage and the generation of beta-amyloid (A beta). This study investigated the mechanism by which LPS causes neuronal damage and found that oxidative stress, neuroinflammation, and Ca2+ overload play important roles in AD. The activation of SOCE-mediated NFAT1-NOX2-NLRP1 inflammasome is involved in LPS-induced neuronal damage and A beta generation. Treatment with inhibitors and scavengers reversed these LPS-induced changes and improved neuronal damage and A beta deposition.