Tim-3, a molecule involved in immune regulation, hinders plaque removal in Alzheimer’s disease. Blocking it in microglia improved brain health in mice, making it a potential treatment target.
Tim-3 is an immune checkpoint molecule known for its role in regulating immunity and inflammation. Recently, it has been linked to late-onset Alzheimer’s disease (AD), though its function in the brain remained unclear. In a study published in Nature, researchers at Mass General Brigham used preclinical models to investigate Tim-3’s role in microglia, the brain’s resident immune cells, and identified it as a potential 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.”
Tim-3’s Function in Microglia
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.
Reference: “Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease” by Kimitoshi Kimura, Ayshwarya Subramanian, Zhuoran Yin, Ahad Khalilnezhad, Yufan Wu, Danyang He, Karen O. Dixon, Udbhav Kasyap Chitta, Xiaokai Ding, Niraj Adhikari, Isabell Guzchenko, Xiaoming Zhang, Ruihan Tang, Thomas Pertel, Samuel A. Myers, Aastha Aastha, Masashi Nomura, Ghazaleh Eskandari-Sedighi, Vasundhara Singh, Lei Liu, Conner Lambden, Kilian L. Kleemann, Neha Gupta, Jen-Li Barry, Ana Durao, Yiran Cheng, Sebastian Silveira, Huiyuan Zhang, Aamir Suhail, Toni Delorey, Orit Rozenblatt-Rosen, Gordon J. Freeman, Dennis J. Selkoe, Howard L. Weiner, Mathew Blurton-Jones, Carlos Cruchaga, Aviv Regev, Mario L. Suvà, Oleg Butovsky and Vijay K. Kuchroo, 9 April 2025, Nature.
DOI: 10.1038/s41586-025-08852-z
Disclosures: Blurton-Jones is a co-founder and consultant for Savanna Biotherapeutics (formally NovoGlia Inc). Selkoe is a founding director of Prothena Biosciences and an ad hoc consultant to Eisai. Suvà is an equity holder, scientific co-founder, and advisory board member of Immunity Therapeutics. Butovsky has a collaboration with GSK and Regulus Therapeutics, receiving research funding from Sanofi and GSK, and honoraria for lectures and consultancy from UCB, Camp4, and Ono Pharma USA. He is also a co-founder of and has an ownership interest in Glial Therapeutics and General Biophysics. Kuchroo has an ownership interest in and is a member of the scientific advisory board for Larkspur Biosciences. He is also a co-founder of and has an ownership interest in Tizona Therapeutics and Bicara Therapeutics.
Funding: This work was supported by the NIH-NIAID (P01 AI073748, R01 AI144166, P01 AI056299, P01 AI056299), NIH-NIA (R01 AG080992, R01AG054672, R01AG051812, R01AG075509, R21AG076982, R01 AG082704, U19AG069701), and Cure Alzheimer’s Fund (2021, 2022, ApoE Consortium, Neuroimmune Consortium), NIH-NINDS (R01NS088137), NIH-NEI (R01EY027921), BrightFocus Foundation (2020A016806). The UCI-ADRC iPSC core is funded by NIH AG066519.
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