To understand the relationship between androgens and AD, first author Emily Rosario looked at the effect of androgen depletion on pathology in the triple transgenic AD mouse model (APPswe, PS1M146V, tauP301L) created in coauthor Frank LaFerla’s lab. When the researchers removed the animals’ testes at 3 months of age, the gonadectomized mice showed an increase in Aβ load in the brain at 7 months compared to their unaltered littermates. The accelerated Aβ accumulation was prevented by starting testosterone replacement at the time of surgery. Parallel to the Aβ accumulation, the researchers detected more severe deficits in a spontaneous alternation test in androgen-deprived mice. The behavior, which relies on hippocampal-dependent working memory, was also normalized by hormone replacement.

The pathway linking testosterone and Aβ accumulation is unknown, but the results are consistent with an increase in Aβ that was observed in normal rats after gonadectomy (Ramsden et al., 2003).

“Our findings extend a growing literature indicating that androgens can benefit cognitive abilities significantly by mechanisms that may include a reduction in Aβ levels,” the authors conclude. “The findings not only demonstrate a significant role of androgen depletion in AD pathogenesis, but also predict that androgen-based therapeutics may function effectively in the prevention of AD,” they write.—Pat McCaffrey.

Reference:
Rosario ER, Carroll JC, Oddo S, Laferla FM, Pike CJ. Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J Neurosci. 2006 Dec 20; 26(51):13384-9. Abstract