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- W2789241750 abstract "Mutations in Presenilins (PS) cause early onset familial Alzheimer's disease (AD) by mechanisms that have not been fully elucidated. Modulating the activity of PS and the gamma-secretase complex is a possible therapy for AD, and thus a better understanding of PS function in the central nervous system (CNS) is needed. PS1 and PS2 are expressed in many CNS cell types including microglia, the innate immune cell of the brain. We sought to investigate the impact of gamma-secretase inhibition and specific PS deficiency in microglia. We measured Lipopolysaccharide (LPS) induced cytokine release by primary murine microglia exposed to the pharmacological gamma-secretase inhibitor, DAPT. Similar experiments were performed in microglia made deficient in either PS1 or PS2 using short-hairpin RNA (shRNA) as well as in microglia isolated from PS2 knockout mice. Gamma-secretase activity was measured by a luciferase expression based amyloid precursor protein cleavage assay. Expression of PS protein in microglia of AD patient brain autopsy tissue was evaluated by immunohistochemistry. DAPT augments the release of pro-inflammatory cytokines induced by LPS in microglia. To clarify if both PS participate in the gamma-secretase complex that modulates the microglia inflammatory response, we used shRNA to knockdown specific PS expression. PS1 knockdown leads to both elevated PS2 protein levels and increased gamma-secretase activity. PS2 deficiency in microglia leads to elevated PS1 protein but dramatically decreased gamma-secretase activity. Similar to the impact of DAPT, PS2 deficiency results in exaggerated pro-inflammatory cytokine release whereas PS1 deficiency does not. PS2 protein and gene expression is increased in microglia activated by interferon-gamma and PS2 expression is enhanced in microglia in AD brain. Gamma-secretase inhibition and PS2 deficiency cause exaggerated pro-inflammatory cytokine release in microglia. PS2 is the predominant gamma-secretase in microglia and is upregulated by pro-inflammatory stimuli. We hypothesize PS2 participates in the negative regulation of pro-inflammatory pathways in microglia and is induced in states of CNS inflammation to curb detrimental inflammatory behavior in the brain." @default.
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- W2789241750 date "2010-07-01" @default.
- W2789241750 modified "2023-09-27" @default.
- W2789241750 title "P4-058: Presenilin 2 is the Predominant Gamma-secretase in Microglia and Regulates Cytokine Release" @default.
- W2789241750 doi "https://doi.org/10.1016/j.jalz.2010.08.118" @default.
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