title: Presenilin 2 is the predominant γ-secretase in microglia and modulates cytokine release.
abstract: Presenilin 1 (PS1) and Presenilin 2 (PS2) are the enzymatic component of the γ-secretase complex that cleaves amyloid precursor protein (APP) to release amyloid beta (Aβ) peptide. PS deficiency in mice results in neuroinflammation and neurodegeneration in the absence of accumulated Aβ. We hypothesize that PS influences neuroinflammation through its γ-secretase action in CNS innate immune cells. We exposed primary murine microglia to a pharmacological γ-secretase inhibitor which resulted in exaggerated release of TNFα and IL-6 in response to lipopolysaccharide. To determine if this response was mediated by PS1, PS2 or both we used shRNA to knockdown each PS in a murine microglia cell line. Knockdown of PS1 did not lead to decreased γ-secretase activity while PS2 knockdown caused markedly decreased γ-secretase activity. Augmented proinflammatory cytokine release was observed after knockdown of PS2 but not PS1. Proinflammatory stimuli increased microglial PS2 gene transcription and protein in vitro. This is the first demonstration that PS2 regulates CNS innate immunity. Taken together, our findings suggest that PS2 is the predominant γ-secretase in microglia and modulates release of proinflammatory cytokines. We propose PS2 may participate in a negative feedback loop regulating inflammatory behavior in microglia.
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington, United States of America. sumie@u.washington.edu
authors.forename: Suman
authors.initials: S
authors.lastname: Jayadev
authors.forename: Amanda
authors.initials: A
authors.lastname: Case
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Eastman
authors.forename: Huy
authors.initials: H
authors.lastname: Nguyen
authors.forename: Julia
authors.initials: J
authors.lastname: Pollak
authors.forename: Jesse C
authors.initials: JC
authors.lastname: Wiley
authors.forename: Thomas
authors.initials: T
authors.lastname: Möller
authors.forename: Richard S
authors.initials: RS
authors.lastname: Morrison
authors.forename: Gwenn A
authors.initials: GA
authors.lastname: Garden
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D053766:Presenilin-2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D053764:Presenilin-1; D053766:Presenilin-2; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases