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

Objective: To test whether female gonadal hormone status and estrogen modulate the metabolism of A beta peptides in vivo. Background: 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 in postmenopausal women is associated with decreased risk for AD or delay in disease onset or both. 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. 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+low-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: Prolonged ovariectomy resulted in uterine atrophy and decreased serum E2 levels and was associated with a pronounced increase in brain A beta levels. Total 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 addition, both doses of E2 significantly reversed the ovariectomy-induced increase 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 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. In addition, our finding that E2 treatment is associated with diminution of brain A beta levels suggests that modulation of A beta metabolism may be one of the ways by which estrogen replacement therapy prevents or delays the onset of AD or both in postmenopausal women.