Objective: To test whether female gonadal hormone status and estrogen modulate the metabolism of Aβ peptides in vivo. Background: AD is a neurodegenerative disorder characterized by accumulation of aggregated forms of the 40- and 42-amino acid Aβ peptides (Aβ40 and Aβ42). 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. 17β-estradiol (E2) was shown to reduce the release of Aβ 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 Aβ40 and Aβ42 levels were assessed using Aβ40 and Aβ42-specific ELISA assays. Results: Prolonged ovariectomy resulted in uterine atrophy and decreased serum E2 levels and was associated with a pronounced increase in brain Aβ levels. Total brain Aβ 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 Aβ levels. The high-dose E2 treatment did not lead to a further decrease in brain Aβ beyond that observed with the low-dose E2 treatment. Conclusions: Our results infer that cessation of ovarian estrogen production in postmenopausal women might facilitate Aβ deposition by increasing the local concentrations of Aβ40 and Aβ42 peptides in brain. In addition, our finding that E2 treatment is associated with diminution of brain Aβ levels suggests that modulation of Aβ metabolism may be one of the ways by which estrogen replacement therapy prevents or delays the onset of AD or both in postmenopausal women.

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