Tim-3 is an immune checkpoint molecule involved in immunity and inflammation recently linked to late-onset Alzheimer's disease (AD), but its role in the brain was unknown until now. In a paper published in Nature, researchers from Mass General Brigham used preclinical models to uncover Tim-3's role in microglia, the brain's resident immune cells, and have identified it as a promising therapeutic target for Alzheimer's disease.

"Immune checkpoint inhibitors have revolutionized cancer immunotherapy, and it is exciting that we might be able to repurpose them to treat Alzheimer's disease," said senior author Vijay Kuchroo, PhD, DVM, of the Gene Lay Institute of Immunology and Inflammation at Brigham and Women's Hospital and Massachusetts General Hospital, founding members of the Mass General Brigham healthcare system. "Microglia are pivotal in neuroinflammation and neurodegeneration, and therapeutic targeting of Tim-3 in microglia may alter them to an optimal state to fight the disease pathology in AD."

Using a mouse model of AD, the Kuchroo lab together with Oleg Butovsky lab, at the Ann Romney Center for Neurologic Diseases at BWH, determined that Tim-3 is only expressed in microglia in the central nervous system, where it helps the cells maintain a healthy state of homeostasis. Tim-3 can also, however, prevent the brain from effectively clearing out the toxic plaques that accumulate during AD. The researchers found that deleting Tim-3 helped kickstart plaque removal by prompting the microglia to eat up more of the plaques, while also producing anti-inflammatory proteins to reduce neuroinflammation, and limiting cognitive impairment.

Over a half-dozen clinical trials are currently testing therapeutics that target Tim-3 to treat patients with immunotherapy-resistant cancers. According to the authors, the new study highlights the therapeutic potential of adapting these treatments to enhance plaque clearance and mitigate neurodegeneration in Alzheimer's disease.

Kimura K, Subramanian A, Yin Z, Khalilnezhad A, Wu Y, He D, Dixon KO, Chitta UK, Ding X, Adhikari N, Guzchenko I, Zhang X, Tang R, Pertel T, Myers SA, Aastha A, Nomura M, Eskandari-Sedighi G, Singh V, Liu L, Lambden C, Kleemann KL, Gupta N, Barry JL, Durao A, Cheng Y, Silveira S, Zhang H, Suhail A, Delorey T, Rozenblatt-Rosen O, Freeman GJ, Selkoe DJ, Weiner HL, Blurton-Jones M, Cruchaga C, Regev A, Suvà ML, Butovsky O, Kuchroo VK.
Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease.
Nature. 2025 Apr 9. doi: 10.1038/s41586-025-08852-z