Effect of 5α-androstane-3α,17β-diol on ERK and MKP3 in a mouse model of Alzheimer's Disease

Abstract

Alzheimer's Disease (AD) is more common in women, while low free testosterone has been associated with increased AD risk in men. However, treatment with testosterone has yielded mixed results in improving AD-related cognitive decline. Previous in vitro studies have shown that a major neurometabolite of testosterone: 5α-androstane-3α,17β-diol (3α-diol) inhibited the prolonged extracellular signal-regulated kinase (ERK) phosphorylation associated with oxidative stress. The role of 3α-diol in vivo remains unknown. We therefore examined the effects of continuous 3α-diol treatment on protein markers associated with AD progression in a triple transgenic (3xTg) mouse model. 3-month-old wild-type and 3xTg mice received subcutaneous implants of a 1 cm long Silastic capsule containing either 3α-diol dipropionate, or a blank capsule. Brains were collected at 6 and 9 months of age to analyze changes in expression of hippocampal ERK, MAP Kinase Phosphatase 3 (MKP3), plus phosphorylated (Ser202) and total tau. 3α-diol had no significant effect on the ratio of phosphorylated: total tau, at either age. No significant differences in ERK phosphorylation were observed at 6 months, but at 9 months sex and genotype-dependent differences were observed, with 9-month 3xTg females exhibiting higher ERK phosphorylation as well as markedly higher MKP3 expression. Treatment with 3α-diol had no effect on ERK phosphorylation, but significantly reduced MKP3 at 9 months, to levels indistinguishable from those observed in 3xTg males. 3α-diol may contribute to sex differences in AD susceptibility.