2024 Alzheimer's Association Research Fellowship (AARF)

The role of the CXCL9-11/CXCR3 cascade in frontotemporal dementia pathology

Does the CXCL9-11/CXCR3 signaling pathway contribute to brain changes in frontotemporal dementia?

Nazaret Gamez, Ph.D.
The Methodist Hospital Research Institute
Houston, TX - United States

Background

Frontotemporal dementia (FTD) refers to a group of degenerative diseases characterized by progressive nerve cell loss in the brain’s frontal lobes (areas behind your forehead) or temporal lobes (regions behind your ears). Developing FTD treatments has been challenging because different forms of FTDs involve different symptoms and different genetic changes. As a result, researchers are looking for common biological mechanisms that can be targeted in therapies for multiple FTD varieties.

One of these common biological mechanisms is brain inflammation caused by changes in the immune system and immune cells in the brain. Some studies suggest that when special signaling factors, CXCL9-11 and CXCR3 attach to each other they act like a signal to recruit other immune cells to an area of inflammation. Dr. Nazaret Gamez and colleagues have previously identified CXCL9-11/CXCR3 signaling as highly active in FTD, however this contributes to brain changes is unknown.

Research Plan

To address this question, the research team will begin by measuring the amount of CXCL9-11/CXCR3 in the blood and the brain of individuals with FTD to see if there is difference compared to individuals without FTD. Next, the researchers will explore which types of brain cells are responsible for making CXCL9-11/CXCR3 proteins. Finally, the research team will use a drug to prevent CXCL9-11 from attaching to CXCR3 in a genetically engineered mouse model that produces FTD-like brain changes. Dr. Gamez believes that when the  drug blocks the attachment of CXCL9-11 to CXCR3,  the cells will be unable to send recruitment signals to other immune cells. The research team  will then measure brain changes in the genetically engineered FTD-like mice with and without the drug to see if there is a change.

Impact

Results from this study may help us better understand the role of CXCL9-11/CXCR3 on brain inflammation in FTD and may provide additional targets for potential treatments.