SOCE-mediated NFAT1-NOX2-NLRP1 inflammasome involves in lipopolysaccharide-induced neuronal damage and Aβ generation.

Abstract

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 β-amyloid (Aβ) 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 (250µg/kg) exposure for 14days was used to induce cognitive dysfunction in mice and LPS (20µg/ml) exposure for 48h 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 Aβ 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 Aβ 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 Aβ generation.