Grant: Canada Postdoctoral Research Award (CPRA) program

Alzheimer's disease (AD) is a severe brain disorder that slowly worsens over time, resulting in memory loss and thinking impairment. It affects women more than men, with nearly two-thirds of cases found in females. The disease is associated with two harmful protein changes in the brain, including buildup of amyloid (AB42) and abnormal forms of tau, which together damage communication between brain cells. One key protein involved in this process is called mGluR5, which essentially assists brain cells communicate and supports learning and memory. In Alzheimer's disease, toxic amyloid proteins bind to mGluR5, disturbing brain signaling and harming brain cells. Our results showed us that blocking mGluR5 improves memory and reduces brain damage in male mice with Alzheimer's, but not in females. This shows there are important biological differences between the sexes in how this protein works. Early studies suggest that proteins such as TRIM9, and the estrogen receptor (ERa) may explain these differences. In fact, amyloid proteins appear to attach to mGluR5 only in male brain tissue, not female, across several species. We believe these sex-specific differences in mGluR5 interactions may explain why men and women experience Alzheimer's differently. Our research will: (1)Investigate the molecular and genetic causes for these differences. (2)Test whether a new drug that enhances mGluR5 activity can improve memory and reduce disease signs in both male and female Alzheimer's mice. By uncovering how sex affects brain signaling in Alzheimer's, this work may pave the way to more precise and effective treatments helping ensure that both men and women benefit equally.