[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)].

Conclusion: 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.