2022 Alzheimer's Association Research Grant (AARG)

The Role of Cannabinoid Receptor 2 in the Clearance of Tau by Microglia

What are the biological mechanisms by which immune cells in the brain help clear out abnormal tau?

Valerie Joers, Ph.D.
University of Florida
Gainesville, FL - United States

Background

The protein tau helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. During Alzheimer’s, immune cells in the brain, known as microglia, can become activated in response to the brain changes and release substances that increase the activity of the immune system.  These changes may lead to nerve cell damage.

Researchers are investigating the role of a nerve pathway in the brain known as the endocannabinoid system. This system comprises nerve cells that respond to a class of drugs known as cannabinoids. Cannabinoids can come from external sources (such as cannabis) or from naturally occurring molecules in the brain (endocannabinoids). Several studies have shown that activation of the endocannabinoid system in the brain can reduce inflammation and potentially reduce damage to nerve cells.

Dr. Valerie Joers and colleagues are studying a receptor or “docking site” on the surface of the microglia cells called the cannabinoid type 2 (CB2) receptor. CB2 appears to be involved in how the endocannabinoid system responds to and impacts the immune function, but little is known about how CB2 regulates microglial response to abnormal tau in the brain.

Research Plan

Dr. Joers and team will study how CB2 receptors on microglia may mediate the interaction between microglia and tau in the brains of genetically engineered Alzheimer’s-like mice. Using brain tissue from Alzheimer’s-like mice grown in laboratory dishes, the researchers will investigate the role of CB2 in the biology that removes abnormal tau. They will use sophisticated imaging and quantification techniques to measure tau in the brain tissue and compare findings in mice with deficient levels of CB2 to mice with normal levels of CB2. Next, the team will identify the CB2-mediated mechanisms associated with how the abnormal tau is removed from the brain, using the Alzheimer’s-like mice and other models to inform the biological underpinnings. 

Impact

The results of this project may advance our understanding of biological underpinnings of how the immune system and the cell-to-cell communication systems may interact. The findings from this work may highlight the CB2 receptor as a therapeutic target against brain diseases such as Alzheimer’s and open up a new pathway for therapy development.