Grant: Project Grant

Alzheimer's disease is a devastating neurodegenerative disorder associated with progressive cognitive decline. Out of 36 million patients worldwide, approximately 60% of all Alzheimer's disease patients are female. Yet the majority of research on Alzheimer's disease is conducted on male mice, or cells which are not separated by sex. This increases the likelihood of missing important sex-specific differences in male and female Alzheimer's disease treatments. We have shown that blockade of an important neurotransmitter receptor, metabotropic glutamate receptor 5 (mGluR5), rescues memory and Alzheimer's disease pathology in male, but not female, Alzheimer's disease preclinical mouse models. We have recently discovered that this occurs because one of the toxic mediators of Alzheimer's disease (beta-amyloid) does not utilize mGluR5 in female brain to mediate Alzheimer's disease pathology. We now have data to suggest that cell types in the brain other than neurons (astrocytes and microglia) contribute to Alzheimer's disease disease progression and might be good targets for treating Alzheimer's disease. Moreover, there is a link between other neurotransmitter receptors in the coordination of Alzheimer's disease progression. We will pursue the hypothesis that: mGluR5 sex-specific protein interactions, mGluR5-dependent differences in glial cell-mediated inflammation and dysregulated mGluR5/m1mAChR signaling can be targeted to prevent Alzheimer's disease progression. This work will provide important new understanding of the role of sex-specific differences in the underlying mechanisms that contribute to the development of Alzheimer's disease. There has been a failure to account for sex-specific differences in pharmacological activity at potential Alzheimer's disease drug targets. Our goal is to understand sex-specific difference in the progression of Alzheimer's disease and provide tailored approaches that enable us to more effectively treat Alzheimer's disease in both sexes.