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Updated: Jun 5, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Presenilin 2 is the predominant γ-secretase in microglia and modulates cytokine release
Suman Jayadev1, Amanda Case, Alison J Eastman
1Department of Neurology, University of Washington, Seattle, Washington, United States of America. sumie@u.washington.edu
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.
Insights
Presenilin 2 (PS2) regulates neuroinflammation in the brain. This study shows PS2 is the main enzyme in microglia, controlling the release of inflammatory cytokines and potentially regulating brain immune responses.
Area of Science:
- Neuroimmunology
- Molecular Neuroscience
- Cellular Neuroscience
Background:
- Presenilin 1 (PS1) and Presenilin 2 (PS2) are key components of the gamma-secretase complex, involved in cleaving amyloid precursor protein (APP).
- PS deficiency in mice leads to neuroinflammation and neurodegeneration, independent of amyloid beta (Aβ) accumulation.
- The role of PS in central nervous system (CNS) innate immune cells and neuroinflammation remains unclear.
Purpose of the Study:
- To investigate the hypothesis that presenilins influence neuroinflammation via their gamma-secretase activity in CNS innate immune cells.
- To determine whether PS1, PS2, or both mediate the gamma-secretase activity and subsequent cytokine release in microglia.
Main Methods:
- Primary murine microglia were treated with a pharmacological gamma-secretase inhibitor.
- Short hairpin RNA (shRNA) was used to knockdown PS1 and PS2 in a murine microglia cell line.
- Gamma-secretase activity, pro-inflammatory cytokine release (TNFα, IL-6), and PS2 gene/protein expression were measured.
Main Results:
- Inhibition of gamma-secretase led to exaggerated release of TNFα and IL-6 in response to lipopolysaccharide.
- PS2 knockdown significantly reduced gamma-secretase activity and augmented pro-inflammatory cytokine release.
- PS2 gene transcription and protein levels increased in microglia following pro-inflammatory stimuli.
Conclusions:
- Presenilin 2 (PS2) is identified as the predominant gamma-secretase in microglia, regulating CNS innate immunity.
- PS2 modulates the release of pro-inflammatory cytokines, suggesting a role in microglial inflammatory responses.
- PS2 may participate in a negative feedback loop controlling microglial inflammatory behavior.
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