Role of Checkpoint Molecules TIM-3 and LAG-3 in Microglial Function in Alzheimer’s Disease


Microglial cells, the primary immune cells and the sensor of the brain, play a pivotal role in the maintenance of brain homeostasis. In adult and aging brain, many of the phagocytic and proinflammatory functions of the microglia are curtailed so that the microglia can develop a homeostatic phenotype. But this behavior of microglial cells comes at a cost, in that homeostatic microglia are not readily able to clear amyloid beta plaques in the aging brain. This results in a buildup of plaque burden and generation of neurofibrillary tangles, which contribute to disease pathology observed in Alzheimer’s disease (AD). There is a gap in our knowledge about how microglial function is maintained in the healthy brain and is prone to dysregulation in AD. During the previous grant cycle, we observed that one of the checkpoint molecules, TIM-3, that we discovered suppresses immune cells also is expressed developmentally on microglial cells, and inhibits their phagocytic behavior. TIM-3 also has been linked to susceptibility to AD in a recent genetic analysis, thus raising the issue of how TIM-3 might be regulating microglial behavior and contributing to the development of AD. Our preliminary studies show that a genetic deletion of TIM-3 experimentally in microglial cells results in activation of microglia, an increase in their phagocytic behavior and clearance of plaque burden in AD disease models, without promoting inflammation linked to Disease Associated Microglia (DAM), which appear in the brains of AD patients. These data support genetic linkage studies and show the importance of TIM-3 in regulating disease pathology in AD by affecting microglial function. In addition to TIM-3, we now find that microglial cells express another checkpoint molecule widely studied in the immune system called LAG-3. The two checkpoints, TIM-3 and LAG-3, are expressed together and function together to suppress immune responses. We suspect that TIM-3 and LAG-3 may be working together to limit microglial activation, and thereby limiting clearance of amyloid beta plaques as well. In this study, we propose to investigate how TIM-3 and LAG-3 may work together and limit clearance of accumulating plaque load in AD patients.  


Since there are antibodies to TIM-3 (sabatolimab) in clinical trials for cancer and anti-LAG-3 antibodies already are approved by the FDA for treatment of melanoma, one can envision that our data may provide impetus for testing drug candidates that can be repurposed for the treatment of AD. 

Funding to Date



Studies of Innate Immune Pathology, Translational


Vijay K. Kuchroo, D.V.M., Ph.D.