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Notably, our results also underscore the need for more studies addressing whether novel AD therapies aimed at enhancing TREM2 activity could have adverse, as opposed to beneficial, effects on AD pathogenesis. Credit: Neuroscience News<\/p>\nSummary: A new study has identified a mutation in the TREM2 gene that disrupts the brain\u2019s ability to clear toxic amyloid plaques, increasing Alzheimer\u2019s disease risk. The mutation, called T96K, keeps the TREM2 gene in an overactive state that paradoxically weakens microglial \u201ccleanup\u201d activity, especially in females.<\/p>\n
Using genetically modified mice, researchers discovered that these overactive microglia failed to respond effectively to amyloid buildup, leaving the brain more vulnerable to neurodegeneration. The findings reveal that both excessive and deficient TREM2 activity can harm brain health, offering crucial insights for designing safer Alzheimer\u2019s therapies.<\/p>\n
Key Facts:<\/p>\n
New Mutation Identified: The TREM2-T96K gain-of-function mutation impairs microglial ability to remove amyloid plaques.Sex-Specific Effect: The mutation reduced microglial protection and plaque clearance in female Alzheimer\u2019s model mice.Therapeutic Implications: Enhancing TREM2 activity may not always be beneficial and could worsen Alzheimer\u2019s pathology.<\/p>\n
Source: Mass General<\/p>\n
Dominika Pilat, PhD, and\u00a0Ana Griciuc, PhD, of the\u00a0Department of Neurology\u00a0at Massachusetts General Hospital are the lead and senior authors of a paper published in\u00a0Neuron,\u00a0\u201cThe Gain-of-Function\u00a0TREM2-T96K Mutation Increases Risk for Alzheimer\u2019s Disease by Impairing Microglial Function.\u201d<\/p>\n
Q: How would you summarize your study for a lay audience?<\/p>\n
Our team wanted to understand how immune cells of the brain, called microglia, contribute to Alzheimer\u2019s disease (AD) pathology. It\u2019s known that subtle changes, or mutations, in genes expressed in microglia are associated with an increased risk for developing late-onset AD.<\/p>\n
Notably, our results also underscore the need for more studies addressing whether novel AD therapies aimed at enhancing TREM2 activity could have adverse, as opposed to beneficial, effects on AD pathogenesis. Credit: Neuroscience News<\/p>\n
Our study focused on one such mutation in the microglial gene\u00a0TREM2,\u00a0an essential switch that activates microglia to clean up toxic amyloid plaques (abnormal protein deposits) that build up between nerve cells in the brain.<\/p>\n
This mutation, called T96K, is a \u201cgain-of-function\u201d mutation in\u00a0TREM2, meaning it\u00a0increases\u00a0TREM2\u00a0activation and allows the gene to remain super active.<\/p>\n
Through our research, we explored how this mutation impacts microglial function to increase risk for AD. We generated a mutant mouse model carrying the mutation, which was bred with a mouse model of AD to have brain changes consistent with AD.<\/p>\n
We found that in female AD mice exclusively, the mutation strongly reduced the capability of microglia to respond to toxic amyloid plaques, making these cells less protective against brain aging.<\/p>\n
Q: What question\u00a0were you investigating?<\/p>\n
We asked whether the T96K mutation in the\u00a0TREM2\u00a0gene helps or hurts the pathogenesis of Alzheimer\u2019s disease. This led us to investigate how this mutation affects microglial function in mouse models of AD.<\/p>\n
Q: What methods or approach did you use?<\/p>\n
To analyze the role of this mutation in Alzheimer\u2019s disease, we combined studies of human genes, a novel\u00a0TREM2-T96K mouse model, and lab tests on microglial cells. To examine the brain tissue, we used an optical imaging technique called confocal microscopy and protein tracking tools, including ELISA.<\/p>\n
Finally, we used single-cell RNA sequencing of microglia isolated from the mouse brain and bioinformatic analysis to map out exactly how the T96K mutation changes the microglia activity over time.<\/p>\n
Q: What did you find?<\/p>\n
Our study is the first to show that a gain-of-function mutation in\u00a0TREM2\u00a0(not just a loss-of-function mutation) is associated with Alzheimer\u2019s disease risk, and that it impairs the uptake of toxic amyloid beta (A\u03b2). Additionally, the\u00a0specific T96K mutation we focused on decreased the total area covered by the microglia \u201ccleanup crews\u201d and suppressed their disease-fighting response, specifically in female AD mice.<\/p>\n
Q: What are the implications?<\/p>\n
Our study on\u00a0TREM2\u00a0gain-of-function mutations shifts our understanding of\u00a0TREM2\u00a0function \u2013 not only from a genetic perspective, but also from a therapeutics perspective.These findings should help guide novel therapeutic approaches for the prevention and treatment of Alzheimer\u2019s disease, based on targeting\u00a0TREM2.<\/p>\n
Notably, our results also underscore the need for more studies addressing whether novel AD therapies aimed at enhancing\u00a0TREM2\u00a0activity could have adverse, as opposed to beneficial, effects on AD pathogenesis.<\/p>\n
Q: What are the next steps?<\/p>\n
Future work will focus on investigating the role of\u00a0TREM2\u00a0gain-of-function mutations in modulating immune functions, microglial lipid metabolism and cellular aging in human microglia-like cells and mouse models of Alzheimer\u2019s disease.<\/p>\n
Authorship:\u00a0In addition to Pilat and Griciuc, Mass General Brigham authors include Hoang Le, Dmitry Prokopenko, Chih-Chung Jerry Lin, William A. Eimer, Luisa Quinti, Evan P. Gavrilles, Sheyla N. Garcia, Sara N. Heitman, Danielle McGinty, Murat Cetinbas, Ruslan I. Sadreyev, and Rudolph E. Tanzi.<\/p>\n
Paper cited:\u00a0Pilat, D.J.,\u00a0et al.\u00a0\u201cThe Gain-of-Function\u00a0TREM2-T96K Mutation Increases Risk for Alzheimer\u2019s Disease by Impairing Microglial Function.\u201d\u00a0Neuron.\u00a0DOI:\u00a010.1016\/j.neuron.2025.09.032<\/p>\n
Funding:\u00a0This work was supported by grants from the NIA\/NIH (R01AG073292 to A.G.), Cure Alzheimer\u2019s Fund (A.G. and R.E.T.), Coins for Alzheimer\u2019s Research Trust Fund (A.G.), Freedom Together Foundation (R.E.T.), and BrightFocus Foundation fellowship A2022009F (H.L.). R.S. is supported by NIDDK\/NIH grant P30DK040561.<\/p>\n
Disclosures:\u00a0The authors declare no competing financial or commercial interests. This study was supported by federal and nonprofit funding sources.<\/p>\n
Key Questions Answered:Q: What does the TREM2 mutation do?<\/p>\n
A: The T96K mutation keeps the TREM2 gene overactive, leading microglia to become less effective at clearing amyloid plaques that drive Alzheimer\u2019s disease.<\/p>\n
Q: Why is this discovery significant?<\/p>\n
A: It challenges the long-held assumption that increasing TREM2 activity always helps protect against Alzheimer\u2019s, revealing that too much activation can be just as damaging.<\/p>\n
Q: What are the next research steps?<\/p>\n
A: Scientists plan to explore how TREM2 gain-of-function mutations influence microglial metabolism, immune signaling, and aging, with the goal of refining treatment strategies.<\/p>\n
About this genetics and Alzheimer\u2019s disease research news<\/p>\n
Author: Brandon Chase<\/a> Original Research: The findings will appear in Neuron<\/p>\n","protected":false},"excerpt":{"rendered":"Summary: A new study has identified a mutation in the TREM2 gene that disrupts the brain\u2019s ability to…\n","protected":false},"author":2,"featured_media":221682,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[4012,64,63,9795,336,137,104691,1679,9797,9798,4011,128,134831],"class_list":{"0":"post-221681","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-alzheimers-disease","9":"tag-au","10":"tag-australia","11":"tag-brain-research","12":"tag-genetics","13":"tag-health","14":"tag-mass-general","15":"tag-medicine","16":"tag-neurobiology","17":"tag-neurology","18":"tag-neuroscience","19":"tag-science","20":"tag-trem2"},"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/221681","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/comments?post=221681"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/221681\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media\/221682"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media?parent=221681"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/categories?post=221681"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/tags?post=221681"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
Source: Mass General<\/a>
Contact: Brandon Chase \u2013 Mass General
Image: The image is credited to Neuroscience News<\/p>\n