| Advancing age is the most significant risk factor for the development of Alzheimer's disease (AD), however, which age-related changes underlie this effect remains unclear. In men, one normal consequence of aging is a robust decline in the circulating levels of the sex steroid hormone testosterone. Testosterone depletion leads to functional impairments in androgen-responsive tissues that are often manifested as the clinical syndrome 'androgen deficiency in aging males'. Although the brain is an androgen-responsive tissue unknown is (1) whether brain levels of T decline during aging, and if so, (2) whether low brain T levels place the aging brain at increased risk for AD, and if so (3) what do androgens regulate that may modulate the increased risk for AD. My thesis work investigated these questions and others examining the relationships between sex steroid hormones, advancing age, and development of AD. In Chapters Two and Three we observed that brain levels of androgens but not estrogens are significantly lower in men with moderate to severe AD in comparison to normal men. To examine how low testosterone levels may contribute to AD development we examined androgen regulation of Abeta, a causal factor in the development of AD. In Chapters, Three through Six we investigated the effects of androgens on regulation and development of Abeta pathology. We found that low levels of testosterone, both in humans and a rodent model of male reproductive aging, correlated with increased levels of soluble Abeta. Using a transgenic mouse model of AD we found that depletion of endogenous androgens resulted in increased accumulation of Abeta pathology and behavioral impairments. Replacement of androgens in these mice was able to prevent this increased accumulation. These findings suggest the use of androgen replacement therapy in men with low levels of androgens. |
