Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model.
Much evidence indicates that women have a higher risk of developing Alzheimer's disease (AD) than do men. The reason for this gender difference is unclear. We hypothesize that estrogen deficiency in the brains of women with AD may be a key risk factor. In rapidly acquired postmortem brains from women with AD, we found greatly reduced estrogen levels compared with those from age- and gender-matched normal control subjects; AD and control subjects had comparably low levels of serum estrogen. We examined the onset and severity of AD pathology associated with estrogen depletion by using a gene-based approach, by crossing the estrogen-synthesizing enzyme aromatase gene knockout mice with APP23 transgenic mice, a mouse model of AD, to produce estrogen-deficient APP23 mice. Compared with APP23 transgenic control mice, estrogen-deficient APP23 mice exhibited greatly reduced brain estrogen and early-onset and increased beta amyloid peptide (Abeta) deposition. These mice also exhibited increased Abeta production, and microglia cultures prepared from the brains of these mice were impaired in Abeta clearance/degradation. In contrast, ovariectomized APP23 mice exhibited plaque pathology similar to that observed in the APP23 transgenic control mice. Our results indicate that estrogen depletion in the brain may be a significant risk factor for developing AD neuropathology.
Yue
Xu
X
L. J. Roberts Center for Alzheimer's Research and Haldeman Laboratory for Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA.
Lu
Melissa
M
Lancaster
Techie
T
Cao
Phillip
P
Honda
Shin-Ichiro
S
Staufenbiel
Matthias
M
Harada
Nobuhiro
N
Zhong
Zhenyu
Z
Shen
Yong
Y
Li
Rena
R
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000097:blood / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology; D010587:Phagocytosis; D011863:Radioimmunoassay; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors
D016229:Amyloid beta-Peptides; D004967:Estrogens; D004958:Estradiol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse