An Animal Model for Estrogen-Mediated Plaque Formation

Recent studies show that elderly women on estrogen therapy have a lower risk for developing Alzheimer’s disease (AD). Furthermore, estrogen therapy improves cognitive function in both female patients with early AD and in elderly women without signs of AD. Moreover, removal of the ovaries in rats and mice causes AD-like memory loss that can be reversed by estrogen therapy. There are multiple lines of evidence showing that estrogen enhances the number and function of synapses. These sites of cell-to-cell communication are thought to be modulated by estrogen. Glial cells (astrocytes and microglia) are nonneuronal cells in the brain that appear to be responsible for modulating synapses under the control of estrogen. Neuritic plaques in the brain at autopsy are diagnostic for AD. Mice that have been experimentally modified to produce mutant proteins form AD-like plaques in brain at ten months of age. These studies will test if reducing circulating levels of estrogen, presumably by increasing the activity of glial cells, will further accelerate the formation of neuritic plaques. This finding would provide important information regarding the mechanisms for plaque formation in AD. Furthermore, we will examine whether the process of plaque formation in these animals causes damage to synapses. The importance of this latter finding is that synapses govern cell-to-cell communication. Loss of these structures during accelerated plaque formation in these mice could help explain the loss of mental function in individuals with AD. If successful, these studies would provide a new animal model to test novel theories for the cause of AD and could be used to develop new drugs that act similar to estrogen to prevent and treat AD.