Ovariectomy of young mutant amyloid precursor protein transgenic mice leads to increased mortality.

Alzheimer disease (AD) is a neurodegenerative disease affecting a large percentage of the elderly population. Preventative therapies for AD have been limited; however, epidemiological studies have demonstrated that estrogen replacement therapy may prevent or delay the onset of AD. Therefore, we utilized female mutant amyloid precursor protein transgenic mice (APP(SWE)), as a mouse model of AD-like pathology, to study the long-term effects of estrogen withdrawal. Interestingly, by 8 months of age 58% of the ovariectomized APP(SWE) mice had died, whereas there was no mortality in the sham ovariectomized APP(SWE) mice. This mortality was correlated with estrogen loss only in the APP(SEW) mice since background strain matched ovariectomized wild-type mice had virtually no mortality. Cerebral A beta levels in the surviving APP(SWE) ovariectomized females were increased by 50% compared to the sham ovariectomized APP(SWE) females. However, the levels of A beta in the ovariectomized APP(SWE) mice were still well below those observed in 2-year-old APP(SWE) mice that had A beta plaques. Therefore, the mildly increased A beta levels were not the suspected cause of death in these ovariectomized mice. Previous studies have demonstrated increased mortality in mice overexpressing mutant or wildtype APP independent of A beta accumulation; thus, estrogen withdrawal may potentiate this phenotype associated with APP overexpression.