Presenilin 2 deficiency facilitates Aβ-induced neuroinflammation and injury by upregulating P2X7 expression

Accumulating evidence suggests that beta-amyloid (A beta)-induced neuroinflammation plays a prominent and early role in Alzheimer's disease (AD). In this study, we demonstrated that Presenilin 2 (PS2) deficiency facilitates A beta-induced neuroinflammation and injury by upregulating P2X7 expression both in vitro and in vivo. PS2 knockout mice demonstrated increased cognitive impairments and cerebral injury. PS2 deficiency increased the expression of P2X7 both in neurons and microglial cells. Furthermore, extracellular ATP also increased in both A beta-treated and untreated PS2 knockout microglial cells. Notably, A beta-induced classical proinflammatory cytokines such as IL-1 beta, IL-1 alpha and TNF-alpha were increased in PS2 knockout microglial cells, suggesting a potential role for PS2 in the regulation of neuroinflammation. The expression of P2X7 clearly increased in PS2 knockdown BV2 cells. Consistent with in vivo data, A beta-induced IL-1 beta production was also clearly enhanced in PS2 knockdown BV2 cells. Additionally, expression of the transcription factor Sp1 was increased in PS2 knockdown cells. When we treated PS2 knockdown cells with the specific Sp1 inhibitor MIT, we observed that enhanced P2X7 expression was significantly rescued. Taken together, these data suggests that PS2 plays a protective role during A beta-induced neuroinflammation and injury through down-regulation of P2X7 expression.