Summary: New research has revealed that Tim-3, a crucial component of the immune system’s microglia, is involved in how Alzheimer’s disease affects them. Tim-3 typically assists in maintaining brain balance, but it can also stop microglia from removing damaging plaque from Alzheimer’s.
In mouse designs, deleting Tim-3 reprogrammed microglia to reduce plaques more efficiently, lessen swelling, and boost mental function. Scientists are optimistic that Tim-3 inhibitors may be repurposed to cure Alzheimer’s and slow the progression of the disease because they are already being tested in cancer studies.
Important Information
- Tim-3 regulates irritation and memorial clearance by controlling the expression of Tim-3 in brain microglia.
- Medical Target: Eliminating Tim-3 promoted memorial cleanup and reduced cognitive decline in mice.
- Clinical Potential: Tim-3 antagonists used in cancer therapy might be adapted for Alzheimer’s care.
Origin: Mass General
An defense checkpoint protein involved in inflammation and resistance was lately linked to late-onset Alzheimer’s disease ( AD), but its exact position in the head was undetermined.
Experts from Mass General Brigham used experimental models to study Tim-3’s part in microglia, the body’s native immune cells, in a document that appeared in Nature. They have since identified it as a promising therapeutic target for Alzheimer’s disease.
Older 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, said:” Immune checkpoint inhibitors have revolutionized cancer immunotherapy, and it is interesting that we might be able to repackage them to behave Alzheimer’s disease.
” Microglia are essential to neuroinflammation and neurodegeneration, and the therapeutic targeting of Tim-3 in microglia may make them go from strength to strength in the fight against the disease pathology of AD.”
The Kuchroo lab and Oleg Butovsky lab at BWH, Ann Romney Center for Neurologic Diseases, used a mouse model of AD to discover that Tim-3 is only expressed in microglia in the central nervous system, where it aids the cells in maintaining a healthy state of homeostasis.
Tim-3 may also hinder the brain from effectively removing the toxic plaques that accumulate during AD. The researchers discovered that deleting Tim-3 helped kickstart plaque removal by causing the microglia to produce anti-inflammatory proteins to lessen neuroinflammation and halt cognitive impairment.
Therapeutics that target Tim-3 are being tested in over a half-dozen clinical trials to treat cancer patients who are immunotherapy-resistant.
The authors claim that the new study highlights the therapeutic potential of adapting these medications to reduce Alzheimer’s disease neurodegeneration and increase plaque clearance.
Authors include Kimitoshi Kimura, Ayshwarya Subramanian, Zhuoran Yin, Ahad Khalilnezhad, Yufan He, Karen Dixon, Udbhav Kasyap Chitta, Xiaokai Ding, Niraj Adhikari, Isabell Guzchenko, Xiaoming Zhang, Ruihan Tang, Thomas Pertel, Aastha Aastha, Masashi Nomura, Lei Samuel A. Myers, Ghazaleh Eskandari-Sedighi, Vasundhara Singh, Toni Delorey, Orit Rosenblatt-Rosen, Gordon J. Freeman, Mathew Blurton-Jones, Carlos Cruchaga, and Aviv Regev are other authors.
Disclosures: Blurton-Jones is a co-founder and consultant for Savanna Biotherapeutics ( formally NovoGlia Inc. ). Selkoe serves as Eisai’s ad hoc consultant and the company’s founding director.
Suvà serves on Immunity Therapeutics ‘ advisory board, scientific co-founder, and equity holder. With the support of Sanofi and GSK, Butovsky has a collaboration with GSK and Regulus Therapeutics, as well as honoraria for lectures and consulting from UCB, Camp4, and Ono Pharma USA.
He co-founded and currently owns both Glial Therapeutics and General Biophysics. Kuchroo is a member of Larkspur Biosciences ‘ scientific advisory board and owns a stake in the company. He co-founded Tizona Therapeutics and Bicara Therapeutics, both of which have him as its controlling shareholder.
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 NIH AG066519 provides funding for the UCI-ADRC iPSC core.
About this research in genetics and Alzheimer’s disease
Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image: The image is credited to Neuroscience News
Original Research: Disclosed access.
Kimura, K., and colleagues ‘” Tim-3 immune checkpoint regulates microglial function and Alzheimer’s disease.” Nature
Abstract
The Tim-3 immune checkpoint regulates the development of microglials and Alzheimer’s disease.
Microglia are the brain’s resident immune cells, and they play crucial roles in neurodevelopment and neuroinflammation.
This study examines the role of the immune-checkpoint molecule TIM-3 ( encoded by HAVCR2 ) in microglia. Late-onset Alzheimer’s disease has recently been linked to TIM-3, which can lead to T cell exhaustion.
However, it is still unclear what its specific role in brain microglia is.
We demonstrate in mouse models that TIM-3 expression is induced by TGF signaling in microglia. Through its carboxy-terminal tail, TIM-3 interacts with SMAD2 and TGFBR2, which promotes TGF-mediated SMAD2 phosphorylation and maintains microglial homeostasis.
A gene-expression profile consistent with the neurodegenerative microglial phenotype ( MGnD ), also known as disease-associated microglia ( DAM ), is caused by the genetic deletion of , Havcr2 , in microglia.
In addition, the microglia-targeted deletion of Havcr2 improves cognitive impairment and lowers amyloid-positive pathology in 5FAD mice ( an Alzheimer’s disease transgenic model )
In 5FAD mice that were deficient in Havcr2, single-nucleus RNA sequencing revealed a subpopulation of , MGnD microglia with increased pro-phagocytic and anti-inflammatory gene expression and decreased pro-inflammatory gene expression.
Single-cell RNA sequencing data from the majority of the microglial clusters in 5FAD mice, who were Havcr2-deficient, confirmed these transcriptomic changes.
Our findings demonstrate that TIM-3 controls TGF signaling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.
