Research ReportEvaluation of the effects of testosterone and luteinizing hormone on regulation of β-amyloid in male 3xTg-AD mice

During normal aging, men experience a significant decline in testosterone levels and a compensatory elevation in levels of gonadotropin luteinizing hormone (LH). Both low testosterone and elevated LH have been identified as significant risk factors for the development of Alzheimer's disease (AD) in men. It is unclear whether changes in testosterone or LH primarily underlie the relationship with AD, and therefore may be a more suitable therapeutic target. To examine this issue, we compared levels of β-amyloid (Aβ) immunoreactivity in male 3xTg-AD mice under varying experimental conditions associated with relatively low or high levels of testosterone and/or LH. In gonadally intact mice, Aβ accumulation increased after treatment with the gonadotropin‐releasing hormone agonist leuprolide, which inhibits the hypothalamic-pituitary-gonadal (HPG) axis and reduces both testosterone and LH levels. In gonadectomized (GDX) mice with low testosterone and high LH, we also observed increased Aβ levels. Treatment of GDX mice with testosterone significantly reduced Aβ levels. In contrast, leuprolide did not significantly decrease Aβ levels and moreover, inhibited the Aβ-lowering effect of testosterone. Evaluation of hippocampal-dependent behavior revealed parallel findings, with performance in GDX mice improved by testosterone but not leuprolide. These data suggest that Aβ-lowering actions of testosterone are mediated directly by androgen pathways rather than indirectly via regulation of LH and the HPG axis. These findings support the clinical evaluation of androgen therapy in the prevention and perhaps treatment of AD in hypogonadal men.

► GnRH agonist leuprolide increased β-amyloid levels in male 3xTg-AD mice. ► Treatment of gonadectomized mice with testosterone not leuprolide reduced β-amyloid. ► Leuprolide inhibited beneficial effects of testosterone in gonadectomized mice. ► These findings support androgen therapy use to prevent Alzheimer's in hypogonadal men.