Estrogenic regulation of memory consolidation: Neural mechanisms and implications for Alzheimer’s disease
The potent estrogen 17beta-estradiol has been increasingly recognized as an important modulator of memory function, and its loss during menopause is thought to contribute to the women’s increased risk of Alzheimer’s disease. However, estrogen therapy in women is tricky because the binding of estrogen receptors in peripheral tissues increases risks of cancer, heart disease, and stroke. To advance the development of treatments that provide the cognitive benefits of estradiol with the side effects of current treatments, my laboratory has focused on pinpointing the molecular mechanisms in the brain through which estradiol facilitates the consolidation of spatial and object recognition memories in mice of both sexes. I will first summarize some of our key findings in female mice demonstrating the involvement of specific cell-signaling pathways in estradiol’s effects on memory consolidation and dendritic spine morphology. Implications of these data for Alzheimer’s disease will be discussed in the context of our studies examining influences of sex, estradiol, and genetic risk factors on memory and brain function in a mouse model of Alzheimer’s disease. Finally, the application of our findings to drug development will be addressed by describing our development of a novel and selective estrogen receptor-specific compound that enhances memory consolidation in a mouse model of menopause.