Abundant evidence suggests that the depletion of estrogen in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD). As a normal consequence of aging, men also exhibit depletion of their primary sex steroid hormone, testosterone. The reduction in men's androgen levels is manifested clinically as impaired function in numerous androgen-sensitive tissues throughout the body, including the brain. Based on recent evidence from our laboratory, we propose that two neural functions of androgens are promotion of neuron viability and regulation of beta-amyloid protein (A-beta). We predict that impairment of these androgen functions occurring as a result of normal, age-related androgen depletion will place the brain at increased risk for the development of Alzheimer's disease. To investigate this hypothesis, we propose three Specific Aims that utilize complementary cell culture, animal model, and human subjects paradigms. In the Aim 1, we will investigate our hypothesis that androgens are endogenous regulators of neuron viability. Proposed studies will assess the role of androgen receptor in neuroprotection as well as elucidate the responsible downstream signaling cascades. Further, we will examine how age-related androgen depletion affects neuronal vulnerability to injury.
In Aim 2, we investigate the hypothesized role of androgens as endogenous modulators of AE, levels. By experimental manipulation of androgen status in animal models, we will evaluate our hypothesis that androgen depletion will result in increased levels of A-beta. Mechanistic studies will evaluate the contributions of androgen receptor activation and androgen regulation of A- beta-catabolizing enzymes. Together, we anticipate that Aims 1 and 2 will establish that androgens have beneficial, protective actions in brain and that androgen depletion places the brain at risk for degeneration and disease.
In Aim 3, we will further evaluate this hypothesis by both investigating how manipulation of androgen status affects progression of AD-like neuropathology in a transgenic mouse model of Alzheimer's disease. and examining the relationships between human aging, brain levels of A-beta and androgens, and AD status. Together, we believe these novel and timely studies will begin an important evaluation of interactions between normal male aging events, neuroprotection, A-beta regulation, and the risk of developing Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDIN (01))
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Miller, Marilyn
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University of Southern California
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Los Angeles
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Rosario, Emily R; Carroll, Jenna C; Pike, Christian J (2012) Evaluation of the effects of testosterone and luteinizing hormone on regulation of ýý-amyloid in male 3xTg-AD mice. Brain Res 1466:137-45
Rosario, Emily R; Chang, Lilly; Head, Elizabeth H et al. (2011) Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer's disease. Neurobiol Aging 32:604-13
Carroll, Jenna C; Rosario, Emily R; Kreimer, Sara et al. (2010) Sex differences in ýý-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure. Brain Res 1366:233-45
Rosario, Emily R; Carroll, Jenna; Pike, Christian J (2010) Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways. Brain Res 1359:281-90
Nguyen, T V; Jayaraman, A; Quaglino, A et al. (2010) Androgens selectively protect against apoptosis in hippocampal neurones. J Neuroendocrinol 22:1013-22
Nguyen, Thuy-Vi V; Yao, Mingzhong; Pike, Christian J (2009) Dihydrotestosterone activates CREB signaling in cultured hippocampal neurons. Brain Res 1298:1-12
Rosario, Emily R; Chang, Lilly; Beckett, Tina L et al. (2009) Age-related changes in serum and brain levels of androgens in male Brown Norway rats. Neuroreport 20:1534-7
Pike, Christian J; Carroll, Jenna C; Rosario, Emily R et al. (2009) Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol 30:239-58
Yao, Mingzhong; Nguyen, Thuy-Vi V; Rosario, Emily R et al. (2008) Androgens regulate neprilysin expression: role in reducing beta-amyloid levels. J Neurochem 105:2477-88
Rosario, Emily R; Pike, Christian J (2008) Androgen regulation of beta-amyloid protein and the risk of Alzheimer's disease. Brain Res Rev 57:444-53

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