Genetic targeting aromatase in male amyloid precursor protein transgenic mice down-regulates beta-secretase (BACE1) and prevents Alzheimer-like pathology and cognitive impairment.
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 beta-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 beta amyloid production and upregulation of NEP activities to enhance bate amyloid degradation.
McAllister
Carrie
C
Banner Sun Health Research Institute, Sun City, Arizona 85351, USA.
Long
Jiangang
J
Bowers
Adrienne
A
Walker
Aaron
A
Cao
Philip
P
Honda
Shin-Ichiro
S
Harada
Nobuhiro
N
Staufenbiel
Matthias
M
Shen
Yong
Y
Li
Rena
R
D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001141:Aromatase / Q000172:deficiency / Q000235:genetics*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004967:Estrogens / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology; D006801:Humans; D007339:Insulysin / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D015260:Neprilysin / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay / Q000379:methods; D018709:Statistics, Nonparametric; D013739:Testosterone / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004967:Estrogens; D012333:RNA, Messenger; D013739:Testosterone; D001141:Aromatase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D015260:Neprilysin; D007339:Insulysin; D010751:Phosphopyruvate Hydratase