Androgen alleviates neurotoxicity of ?-amyloid peptide (A?) by promoting microglial clearance of A? and inhibiting microglial inflammatory response to A?.
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ABSTRACT: AIMS:Lower androgen level in elderly men is a risk factor of Alzheimer's disease (AD). It has been reported that androgen reduces amyloid peptides (A?) production and increases A? degradation by neurons. Activated microglia are involved in AD by either clearing A? deposits through uptake of A? or releasing cytotoxic substances and pro-inflammatory cytokines. Here, we investigated the effect of androgen on A? uptake and clearance and A?-induced inflammatory response in microglia, on neuronal death induced by A?-activated microglia, and explored underlying mechanisms. METHODS:Intracellular and extracellular A? were examined by immunofluorescence staining and Western blot. Amyloid peptides (A?) receptors, A? degrading enzymes, and pro-inflammatory cytokines were detected by RT-PCR, real-time PCR, and ELISA. Phosphorylation of MAP kinases and NF-?B was examined by Western blot. RESULTS:We found that physiological concentrations of androgen enhanced A?42 uptake and clearance, suppressed A?42 -induced IL-1? and TNF? expression by murine microglia cell line N9 and primary microglia, and alleviated neuronal death induced by A?42 -activated microglia. Androgen administration also reduced A?42 -induced IL-1? expression and neuronal death in murine hippocampus. Mechanistic studies revealed that androgen promoted microglia to phagocytose and degrade A?42 through upregulating formyl peptide receptor 2 and endothelin-converting enzyme 1c expression, and inhibited A?42 -induced pro-inflammatory cytokines expression via suppressing MAPK p38 and NF-?B activation by A?42 , in an androgen receptor independent manner. CONCLUSION:Our study demonstrates that androgen promotes microglia to phagocytose and clear A?42 and inhibits A?42 -induced inflammatory response, which may play an important role in reducing the neurotoxicity of A?.
SUBMITTER: Yao PL
PROVIDER: S-EPMC6492702 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
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