Androgen alleviates neurotoxicity of [beta]-amyloid peptide (A[beta]) by promoting microglial clearance of A[beta] and inhibiting microglial inflammatory response to A[beta]

• Published in: CNS neuroscience & therapeutics 2017-11, Vol.23 (11), p.855
• Main Authors: Yao, Peng-Le, Zhuo, Shu, Mei, Hong, Chen, Xiao-Fang, Li, Na, Zhu, Teng-Fei, Chen, Shi-Ting, Wang, Ji-Ming, Hou, Rui-Xing, Le, Ying-Ying
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Androgen receptors; Androgens; Cytokines; Cytotoxicity; Death; Endothelins; Enzyme-linked immunosorbent assay; Geriatrics; Immunofluorescence; Inflammation; Interleukin 1; MAP kinase; Microglia; Neurodegenerative diseases; Neurotoxicity; NF-κB protein; Phosphorylation; Polymerase chain reaction; Tumor necrosis factor; β-Amyloid
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12757

Summary 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[beta]) production and increases A[beta] degradation by neurons. Activated microglia are involved in AD by either clearing A[beta] deposits through uptake of A[beta] or releasing cytotoxic substances and pro-inflammatory cytokines. Here, we investigated the effect of androgen on A[beta] uptake and clearance and A[beta]-induced inflammatory response in microglia, on neuronal death induced by A[beta]-activated microglia, and explored underlying mechanisms. Methods Intracellular and extracellular A[beta] were examined by immunofluorescence staining and Western blot. Amyloid peptides (A[beta]) receptors, A[beta] degrading enzymes, and pro-inflammatory cytokines were detected by RT-PCR, real-time PCR, and ELISA. Phosphorylation of MAP kinases and NF-[kappa]B was examined by Western blot. Results We found that physiological concentrations of androgen enhanced A[beta]42 uptake and clearance, suppressed A[beta]42-induced IL-1[beta] and TNF[alpha] expression by murine microglia cell line N9 and primary microglia, and alleviated neuronal death induced by A[beta]42-activated microglia. Androgen administration also reduced A[beta]42-induced IL-1[beta] expression and neuronal death in murine hippocampus. Mechanistic studies revealed that androgen promoted microglia to phagocytose and degrade A[beta]42 through upregulating formyl peptide receptor 2 and endothelin-converting enzyme 1c expression, and inhibited A[beta]42-induced pro-inflammatory cytokines expression via suppressing MAPK p38 and NF-[kappa]B activation by A[beta]42, in an androgen receptor independent manner. Conclusion Our study demonstrates that androgen promotes microglia to phagocytose and clear A[beta]42 and inhibits A[beta]42-induced inflammatory response, which may play an important role in reducing the neurotoxicity of A[beta].