Presenilin 2 Is the Predominant γ-Secretase in Microglia and Modulates Cytokine Release

Presenilin 1 (PS1) and Presenilin 2 (PS2) are the enzymatic component of the gamma-secretase complex that cleaves amyloid precursor protein (APP) to release amyloid beta (Ab) peptide. PS deficiency in mice results in neuroinflammation and neurodegeneration in the absence of accumulated Ab. We hypothesize that PS influences neuroinflammation through its gamma-secretase action in CNS innate immune cells. We exposed primary murine microglia to a pharmacological gamma-secretase inhibitor which resulted in exaggerated release of TNF alpha 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 gamma-secretase activity while PS2 knockdown caused markedly decreased gamma-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 gamma-secretase in microglia and modulates release of proinflammatory cytokines. We propose PS2 may participate in a negative feedback loop regulating inflammatory behavior in microglia.