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

Abstract

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_SWE mice since background strain matched ovariectomized wild-type mice had virtually no mortality. Cerebral Aβ levels in the surviving APP_SWE ovariectomized females were increased by 50% compared to the sham ovariectomized APP_SWE females. However, the levels of Aβ in the ovariectomized APP_SWE mice were still well below those observed in 2-year-old APP_SWE mice that had Aβ plaques. Therefore, the mildly increased Aβ levels were not the suspected cause of death in these ovariectomized mice. Previous studies have demonstrated increased mortality in mice overexpressing mutant or wild type APP independent of Aβ accumulation; thus, estrogen withdrawal may potentiate this phenotype associated with APP overexpression.