RT Journal Article
SR Electronic
T1 Genetic Targeting Aromatase in Male Amyloid Precursor Protein Transgenic Mice Down-Regulates β-Secretase (BACE1) and Prevents Alzheimer-Like Pathology and Cognitive Impairment
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7326
OP 7334
DO 10.1523/JNEUROSCI.1180-10.2010
VO 30
IS 21
A1 Carrie McAllister
A1 Jiangang Long
A1 Adrienne Bowers
A1 Aaron Walker
A1 Philip Cao
A1 Shin-Ichiro Honda
A1 Nobuhiro Harada
A1 Matthias Staufenbiel
A1 Yong Shen
A1 Rena Li
YR 2010
UL http://www.jneurosci.org/content/30/21/7326.abstract
AB As brain testosterone plays both androgenic and estrogenic actions due to its conversion into estrogen via aromatase naturally, it is unclear that the age-related reduction of testosterone increased risk of Alzheimer's disease (AD) in men is mediated through androgen alone or both androgen and estrogen mechanisms. Our previous studies using a gene-based approach in mouse model to block the conversion of testosterone into estrogen (aromatase gene knock-out, ArKO), found a depletion of estrogen and increase in testosterone endogenously in males. Here, we use crossing the ArKO mice with APP23 transgenic mice, a mouse model of AD, to produce APP23/Ar+/− mice to study the estrogen-independent effect of testosterone on AD. We found a significant reduction in brain plaque formation, improved cognitive function and increase NEP activity in male APP23/Ar+/− mice compared with age-matched male APP23 controls. In addition, we found, for the first time, a reduction of β-secretase (BACE1) enzyme activity, mRNA level and protein expression in the male APP23/Ar+/− mice, suggesting that endogenous testosterone, independent from estrogen, may protect against AD in males via two major mechanisms, downregulation of BACE1 activities at transcriptional level to reduce β amyloid production and upregulation of NEP activities to enhance bate amyloid degradation.