Advancing age is the most significant risk factor for the development of Alzheimer's disease (AD). Men, like women, experience a robust decline in circulating levels of their primary sex steroid hormones, testosterone (T) and its active metabolite dihydrotestosterone (DHT), as a consequence of normal aging. In men, decreases in testosterone leads to functional impairments in androgen-responsive tissues such as bone, muscle, heart, and brain that are often manifested as the clinical syndrome 'androgen deficiency in aging males'. As an androgen-responsive tissue, the brain may also be vulnerable to normal age-related reductions in T and DHT. Recent studies have shown that androgens are neuroprotective and regulate levels (?-amyloid (A?) protein. The goal of proposal is to determine if normal age-related androgen depletion will impair the beneficial actions of androgens, thereby increasing the vulnerability of the aging male brain to the development of AD pathology. The proposed studies will utilize a combination of animal models and analyses of human tissues to investigate the hypothesis that age-related androgen depletion increases the risk for developing AD. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS052143-02
Application #
7184336
Study Section
Special Emphasis Panel (ZRG1-F01-R (20))
Program Officer
Mitler, Merrill
Project Start
2006-02-01
Project End
2008-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$6,315
Indirect Cost
Name
University of Southern California
Department
Type
Other Domestic Higher Education
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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; Villamagna, Angela et al. (2010) Continuous and cyclic progesterone differentially interact with estradiol in the regulation of Alzheimer-like pathology in female 3xTransgenic-Alzheimer's disease mice. Endocrinology 151:2713-22
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
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
Pike, Christian J; Nguyen, Thuy-Vi V; Ramsden, Martin et al. (2008) Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav 53:693-705
Carroll, Jenna C; Rosario, Emily R; Pike, Christian J (2008) Progesterone blocks estrogen neuroprotection from kainate in middle-aged female rats. Neurosci Lett 445:229-32
Carroll, Jenna C; Rosario, Emily R; Chang, Lilly et al. (2007) Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci 27:13357-65
Rosario, Emily R; Carroll, Jenna C; Oddo, Salvatore et al. (2006) Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J Neurosci 26:13384-9