17Alpha-estradiol and 17beta-estradiol Treatments Are Effective in Lowering Cerebral Amyloid-Beta Levels in AbetaPPSWE Transgenic Mice

J Alzheimers Dis. 2002 Dec;4(6):449-57. doi: 10.3233/jad-2002-4601.

Abstract

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. Endogenous and exogenous estrogen both significantly increased the levels of sAbetaPPalpha, the secreted form of AbetaPP. The ratio of Abeta/sAbetaPPalpha, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Abeta lowering effect of 17beta- and 17alpha-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17alpha-estradiol versus 17beta-estradiol may help to develop safe and effective therapeutics.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / analysis*
  • Amyloid beta-Protein Precursor / analysis*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloidosis / pathology*
  • Animals
  • Brain / drug effects*
  • Brain / pathology
  • Estradiol / pharmacology*
  • Estrogen Replacement Therapy*
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Models, Genetic
  • Ovariectomy
  • Stereoisomerism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Estradiol