Androgen alleviates neurotoxicity of β-amyloid peptide (Aβ) by promoting microglial clearance of Aβ and inhibiting microglial inflammatory response to Aβ.

AimsLower 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. MethodsIntracellular 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. ResultsWe 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. ConclusionOur 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 beta.