title: Presenilin 2 deficiency facilitates Aβ-induced neuroinflammation and injury by upregulating P2X7 expression.
abstract: Accumulating evidence suggests that β-amyloid (Aβ)-induced neuroinflammation plays a prominent and early role in Alzheimer's disease (AD). In this study, we demonstrated that Presenilin 2 (PS2) deficiency facilitates Aβ-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 Aβ-treated and untreated PS2 knockout microglial cells. Notably, Aβ-induced classical proinflammatory cytokines such as IL-1β, IL-1α and TNF-α 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, Aβ-induced IL-1β 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 Aβ-induced neuroinflammation and injury through down-regulation of P2X7 expression.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Juliang
authors.initials: J
authors.lastname: Qin
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Jinju
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Liangcai
authors.initials: L
authors.lastname: Gao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Ren
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. mqian@bio.ecnu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Qian
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. bdu.ecnu@gmail.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Du
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D010446:Peptide Fragments; D053766:Presenilin-2; D058486:Receptors, Purinergic P2X7; C074636:amyloid beta-protein (25-35)
keywords: Alzheimer’s disease; P2X7; Presenilin 2; inflammation; β-amyloid