Ovariectomy and 17β-estradiol modulate the levels of Alzheimer's amyloid β peptides in brain

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of aggregated forms of the 40- and 42-amino acid A beta peptides (A beta 40 and A beta 42). Estrogen replacement therapy (ERT) in postmenopausal women is associated with decreased risk for AD and/or delay in disease onset. The mechanism by which estrogen exerts this neuroprotective effect is elusive. 17 beta -estradiol (E2) was shown to reduce the release of A beta peptides by primary neuronal cultures of murine and human origin. To test whether estrogen can modulate the metabolism of A beta peptides in vivo, four experimental sets of guinea pigs were used: intact animals, ovariectomized animals, and ovariectomized animals that received E2 at two different doses. Ovariectomy was associated with a 1.5-fold average increase in total brain A beta levels as compared to intact controls. E2 treatment significantly reversed the ovariectomy-induced increase in brain A beta levels. The high-dose E2 treatment did not lead to further decrease in brain A beta beyond the one observed with the low-dose E2 treatment. Our results infer that cessation of ovarian estrogen production in postmenopausal women might facilitate A beta deposition by increasing the local concentrations of A beta 40 and A beta 42 peptides in brain and suggest that modulation of AP metabolism may be one of the ways by which ERT prevents and/or delays the onset of AD in postmenopausal women. (C) 2000 Elsevier Science Inc. All rights reserved.