Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice

Nov 5, 2016Journal of Alzheimer's disease : JAD

How SOCS3 Changes Activated Brain Immune Cells in a Mouse Model of Alzheimer’s Disease

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Abstract

Microglia in APPswe/PS1dE9 mice exhibit an M1-like phenotype, characterized by the expression of tumor necrosis factor α (TNFα) but not interleukin 6 (IL6).

Alzheimer's disease pathology triggers diverse microglial activations, leading to either immune responses or cytotoxic effects.
Increased oxidative stress and microglial activation were observed starting in middle-aged APPswe/PS1dE9 mice.
Aβ stimulation in microglia resulted in the expression of TNFα, while lipopolysaccharide-stimulated microglia expressed both TNFα and IL6.
Both Aβ-stimulated microglia and microglia from APPswe/PS1dE9 mice expressed suppressor of cytokine signaling 3 (SOCS3).
Reducing SOCS3 expression in Aβ-challenged primary-cultured microglia led to an increase in IL6 production.

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In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer's disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3.

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Role of Suppressor of Cytokine Signaling 3 (SOCS3) in Altering Activated Microglia Phenotype in APPswe/PS1dE9 Mice

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