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The Journal of Neuroscience, December 20, 2006, 26(51):13384-13389; doi:10.1523/JNEUROSCI.2514-06.2006

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Brief Communications
Androgens Regulate the Development of Neuropathology in a Triple Transgenic Mouse Model of Alzheimer's Disease

Emily R. Rosario,¹ Jenna C. Carroll,¹ Salvatore Oddo,³ Frank M. LaFerla,³ and Christian J. Pike^1,2

¹Neuroscience Graduate Program and ²Davis School of Gerontology, University of Southern California, Los Angeles, California 90089, and ³Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92697

Correspondence should be addressed to Dr. Christian J. Pike, Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191. Email: cjpike{at}usc.edu

Normal age-related testosterone depletion in men is a recently identified risk factor for Alzheimer's disease (AD), but how androgen loss affects the development of AD is unclear. To investigate the relationship between androgen depletion and AD, we compared how androgen status affects the progression of neuropathology in the triple transgenic mouse model of AD (3xTg-AD). Adult male 3xTg-AD mice were sham gonadectomized (GDX) or GDX to deplete endogenous androgens and then exposed for 4 months to either the androgen dihydrotestosterone (DHT) or to placebo. In comparison to gonadally intact 3xTg-AD mice, GDX mice exhibited robust increases in the accumulation of ß-amyloid (Aß), the protein implicated as the primary causal factor in AD pathogenesis, in both hippocampus and amygdala. In parallel to elevated levels of Aß, GDX mice exhibited significantly impaired spontaneous alternation behavior, indicating deficits in hippocampal function. Importantly, DHT treatment of GDX 3xTg-AD mice attenuated both Aß accumulation and behavioral deficits. These data demonstrate that androgen depletion accelerates the development of AD-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, our finding that DHT protects against acceleration of AD-like neuropathology predicts that androgen-based hormone therapy may be a useful strategy for the prevention and treatment of AD in aging men.

Key words: testosterone; Alzheimer's disease; dihydrotestosterone; ß-amyloid; spontaneous alternation; neuropathology

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Received June 14, 2006; revised Oct. 11, 2006; accepted Nov. 12, 2006.

Correspondence should be addressed to Dr. Christian J. Pike, Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191. Email: cjpike{at}usc.edu

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