Drug discovery: estrogen-related compounds in mouse models of Alzheimer's disease.

Despite promising epidemiological studies that showed a decreased incidence of Alzheimer disease (AD) in women who used hormone replacement therapy (HRT), the results of the recently released Women's Health Initiative Memory Study has dampened any enthusiasm for the use of HRT in women to prevent or delay the onset of AD. In this position paper, we review these data, along with our own--using estrogens in a transgenic mouse model of AD--and introduce our current working hypothesis and research.

Safe and effective method for chronic 17beta-estradiol administration to mice.

Supraphysiological 17beta-estradiol treatment administered via subcutaneous pellets is commonly used in mice. However, despite its efficacy in eliciting a uterotrophic response, we demonstrate that this regimen also was associated with urine retention, hydronephrosis, and ultimately premature death. To determine a safer yet still effective method to chronically treat mice with 17beta-estradiol, we initiated a placebo-controlled study to treat ovariectomized C57BL/6J mice for 6 weeks with various doses of 17beta-estradiol administered either in their drinking water (0.

Potential use of estrogen-like drugs for the prevention of Alzheimer's disease.

Prior epidemiological studies have shown decreased incidence of Alzheimer's disease among women who were long-term users of hormone replacement therapy. In vitro studies have shown that estrogens possess antioxidant activity, protect cells from the cytotoxic effect of beta-amyloid peptides, and decrease the amyloidogenic processing of the amyloid precursor protein. Animal studies have shown that estrogens promote neuronal plasticity and lead to decreased levels of cerebral beta-amyloid peptide accumulation via decreased amyloidogenic processing of the amyloid precursor protein.

17Alpha-estradiol and 17beta-estradiol treatments are effective in lowering cerebral amyloid-beta levels in AbetaPPSWE transgenic mice.

Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17beta-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid beta (Abeta) levels and amyloid beta-protein precursor (AbetaPP) processing in vivo, Swedish mutant AbetaPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17beta- or 17alpha-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Abeta levels; however, the levels of Abeta were decreased by 27% and 38% in mice treated with 17beta- and 17alpha- estradiol, respectively, with no change in AbetaPP holoprotein.

Increased amyloid- levels in APPSWE transgenic mice treated chronically with a physiological high-fat high-cholesterol diet.

Although plasma cholesterol levels are not generally associated with Alzheimer disease (AD) incidence, in vitro studies have found that increased cellular cholesterol levels are associated with increases in -amyloid (A ) production, with a concomitant decrease in sAPPa, the secreted non amyloidogenic fragment of the amyloid precursor protein (APP). In two previous studies using a mouse model for AD-like pathology, non-physiological high-cholesterol diet has been shown to increase plasma and cerebral cholesterol levels, but have resulted in conflicting results on cerebral A levels. In the present study APPSWE male transgenic mice were fed either a chow diet or a physiological high-fat high-cholesterol Western-type diet until the mice reached 1 year of age.