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

Objective: To test whether female gonadal hormone status and estrogen modul ate the metabolism of A beta peptides in vivo. Background: AD is a neurodeg enerative 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 in postmenopausal women is associated with decreased ri sk for AD or delay in disease onset or both. The mechanism by which estroge n exerts this neuroprotective effect is elusive. 17 beta-estradiol (E2) was shown to reduce the release of A beta peptides by primary neuronal culture s of murine and human origin. Methods: For this purpose, four experimental sets of guinea pigs were used: intact animals, ovariectomized animals (ovx) , and ovariectomized animals that received E2 at two different doses (ovx+l ow-dose E2 and ovx+high-dose E2). Brain A beta 40 and A beta 42 levels were assessed using A beta 40 and A beta 42-specific ELISA assays. Results: Pro longed ovariectomy resulted in uterine atrophy and decreased serum E2 level s and was associated with a pronounced increase in brain A beta levels. Tot al brain A beta in the ovx animals was increased by 1.5-fold on average as compared to intact controls. E2 treatment of ovariectomized animals led to uterine hypertrophy and a dose-dependent increase in serum E2 levels. In ad dition, both doses of E2 significantly reversed the ovariectomy-induced inc rease in brain A beta levels. The high-dose E2 treatment did not lead to a further decrease in brain A beta beyond that observed with the low-dose E2 treatment. Conclusions: Our results infer that cessation of ovarian estroge n 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. In addition, our finding that E2 treatment is associated with diminu tion of brain A beta levels suggests that modulation of A beta metabolism m ay be one of the ways by which estrogen replacement therapy prevents or del ays the onset of AD or both in postmenopausal women.