[Effect of estrogen-depletion and 17beta-estradiol replacement therapy upon rat hippocampus beta-amyloid generation].
OBJECTIVE
To observe the effects of estrogen depletion and 17beta-estradiol replacement therapy upon ratbeta-amyloid (Abeta) generation and the possible related mechanisms.


METHODS
Rat ovaries were ectomized to mimic estrogen-depletion models and then 17beta-estradiol was administered by powdering hormone into soy-free chow as a way of replacement therapy. ELISA was carried out to detect rat hippocampus Abeta levels and alpha- and beta-secretase activities were measured after the experiment. The effects of estrogen depletion and 17beta-estradiol replacement therapy upon beta-secretase (BACE1) and neprilysin (NEP) expression were also analyzed by Western blot.


RESULTS
Ovariectomy significantly decreased estrogen level [(11 + or - 4) pg/ml, P < 0.01] as compared with control group [(21 + or - 8) pg/ml] while 17beta-estradiol administration increased the estrogen level [(63 + or - 13) pg/ml, P < 0.01] in blood. The Abeta40 [(28.5 + or - 4.5) ng/ml, P < 0.01] and Abeta42 [(4.5 + or - 1.2) ng/ml, P < 0.01] levels were higher in ovariectomy group as compared with their respective control group [with Abeta40 (14.4 + or - 2.4) ng/ml and Abeta42 (2.8 + or - 0.4) ng/ml respectively]. But the effects of ovariectomy on Abeta content can be partially reversed by 17beta-estradiol replacement therapy [with Abeta40 (20.3 + or - 3.2)ng/ml, P < 0.01 and Abeta42 (3.8 + or - 0.5)ng/ml, P < 0.01 respectively]. Estrogen depletion decreased alpha-secretase activity (67.5%, P < 0.01) and increased beta-secretase activity (145.8%, P < 0.01) and this effect can be blocked by 17beta-estradiol administration [with alpha-secretase activity to 90.2% (P < 0.01) and beta-secretase activity to 92.4% (P < 0.01)]. Ovariectomy increased BACE1 expression (135.4%, P < 0.01) and decreased NEP expression (40.8%, P < 0.01) and this effect can be partially antagonized by 17beta-estradiol supplementary [with BACE to 103.5% (P < 0.01) and NEP to 88.4% (P < 0.01)].


CONCLUSIONS
Estrogen depletion can increase Abeta generation through the effects of increased beta-secretase activity and decreased alpha-secretase activity. Ovariectomy also increases BACE1 expression and decreases NEP expression. The 17beta-estradiol supplementary can decrease Abeta generation and this may to some extent explain why estrogen replacement therapy can decrease the risk of Alzheimer's disease in postmenopausal women.
Department of Neurology, Henan Provincial People's Hospital, Zhengzhou 450003, China.
Hong-qi
HQ
Yang
Zhi-kun
ZK
Sun
Qiu-huan
QH
Jiang
Qian
Q
Shang
Jun
J
Xu
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D004958:Estradiol / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000172:deficiency; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D000516:alpha-Amylases / Q000378:metabolism; D001614:beta-Amylase / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004967:Estrogens; D004958:Estradiol; D000516:alpha-Amylases; D001614:beta-Amylase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D015260:Neprilysin