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 (AD) patients are female. Yet the majority of research on AD 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 AD. We have previously demonstrated that metabotropic glutamate receptor 5 (mGluR5) has a role in the progression of AD and that blockade of this receptor rescued memory and AD pathology. We now have data which suggests that mGluR5 functions differently in males and females, and that although changes in mGluR5 activity occurs in female AD blockade of this receptor is not effective. One hormonal factor that may play a role in female AD is estrogen and there is evidence that estrogen receptor may interact with mGluR5. The neuroprotective effects of estrogen are well documented by decades of experimental work, and despite the fact that hormone therapy initiated late after menopause increases the risk of dementia in women estrogen remains an attractive target for the treatment of AD. Here, we hypothesize that mGluR5 functions differently in the male and female brain, and that these differences may be due to alterations in estrogen function in females. Thus we propose to 1) investigate sex-specific differences in mGluR5 function in two different mouse models of Alzheimer's disease, specifically the role that estrogen and menopause play in these differences and 2) assess the role of mGluR2/3 activators as an alternative approach to treat AD. Through doing so we hope to more effectively target mGluR5 as a treatment for male and female AD patients, and prevent drugs which may have potential to effectively treat one sex but not the other, from failing in clinical trials due to previously unexplored sex specific differences.