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ANDROGEN REGULATION OF NEUROPATHOLOGY IN ALZHEIMER'S DISEASE
Christian Pike
Andrus Gerontology Center, University of Southern California, Los
Angeles, CA 90089-0191, USA cjpike@usc.edu
Recent studies have established that normal, age-related loss of
testosterone in men is a risk factor for Alzheimer's disease (AD).
Several important but unanswered issues remain, including how testosterone
loss is related to AD and whether androgen therapy can effectively
prevent the disease. Using a variety of experimental paradigms,
we provide new evidence that testosterone loss accelerates accumulation
of beta-amyloid (Abeta), the protein widely believed to initiate
AD pathogenesis. Further, our data suggest that testosterone regulates
Abeta accumulation by a classic genomic mechanism that is dependent
upon activation of the androgen receptor (AR).
In analyses of postmortem human brain samples, we observed age-related
decreases in levels of testosterone and dihydrotestosterone but
in neither estrone nor 17beta-estradiol. In men aged 60-80 years,
brain levels of testosterone were significantly lower in those with
severe AD and mild neuropathological changes in comparison to neuropathologically
normal men. However, this relationship was not apparent in men older
than 80 years, by which time brain levels of androgens were uniformly
low across neuropathological conditions. Interestingly, brain levels
of testosterone inversely correlated with brain levels of soluble
Abeta, suggesting that loss of testosterone may foster neural accumulation
of Abeta.
In parallel rodent studies, normal male aging in brown Norway rats
was associated with androgen depletion in both blood and brain as
well as a corresponding increase in neural accumulation of soluble
Abeta. In the 3xTg-AD triple transgenic mouse model of AD, we found
that gonadectomy-induced androgen depletion in males significantly
accelerated Abeta accumulation and cognitive deficits, effects that
were prevented by testosterone and DHT treatments. Finally, in cell
culture experiments, androgens regulated Abeta levels by an AR-dependent
mechanism involving genomic regulation of the Abeta-catabolizing
enzyme neprilysin.
Together, our data suggest that androgens utilize an AR-dependent
mechanism to regulate brain levels of Abeta, the key event in AD
pathogenesis. Because this relationship appears to be most robust
in early to middle phases of male aging, we suggest that testosterone
therapy for the prevention of AD may be most effective in men younger
than age 80 years.
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