PLSCR1 knockdown reduces inflammatory microglial activation in Alzheimer’s disease by inhibiting NLRP3 inflammasome

Alzheimer’s disease (AD) is the most common form of dementia, whose progression is driven by reactive microglia-mediated neuroinflammation. Phospholipid scramblase 1 (PLSCR1) promotes inflammatory responses and may be involved in the pathogenesis of AD. This study investigated the role of PLSCR1 in the pathogenesis of AD and its involvement in neuroinflammatory processes. In vivo, PLSCR1 knockdown was achieved in APP/PS1 mice to assess its effects on the activation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome in microglia. In vitro, LPS-stimulated BV2 cells were used to determine the effects of PLSCR1 on cell viability and inflammation. PLSCR1 expression was markedly upregulated in the hippocampus of APP/PS1 mice and in LPS-induced BV2 cells. PLSCR1 knockdown improved cognitive dysfunction in APP/PS1 mice. PLSCR1 knockdown downregulated the expression of TNF-α, iNOS, IL-6, and IL-1β, but enhanced the expression of ARG-1, CD206, IL-10, IL-13, and IL-4 in vivo. Exposure to LPS promoted microglial activity, but PLSCR1 knockdown attenuated microglial activity and counteracted the LPS-induced shift of microglia toward a pro-inflammatory phenotype. Furthermore, PLSCR1 knockdown suppressed NLRP3 inflammasome activation in microglia in vivo and in vitro. These findings identify PLSCR1 as a key driver of neuroinflammation and cognitive decline in AD, which activates the NLRP3 inflammasome in microglia, highlighting PLSCR1 as a potential therapeutic target.