{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTREM2 is an innate immune receptor expressed predominantly on microglia whose genetic variants have been robustly associated with several neurodegenerative disorders. Homozygous loss‐of‐function mutations cause early‐onset dementia and Nasu–Hakola disease, whereas heterozygous missense variants (for example, R47H) substantially increase the risk for late‐onset Alzheimer’s disease and even frontotemporal dementia. Such findings underscore that proper TREM2 function is critical for brain health and that even partial loss of its function may dysregulate neuroimmune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, TREM2 plays a pivotal role in modulating microglial responses. It promotes phagocytosis, supports cell survival, and is essential for the transition of microglia from a homeostatic state to a disease‐associated phenotype. Furthermore, deficiency in TREM2 function impairs microglial clustering around amyloid plaques, disrupts intracellular signaling pathways (including mTOR‐dependent energetics), and leads to aberrant autophagy, all of which contribute to the neurodegenerative process."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to regulating phagocytosis and inflammatory responses, TREM2 directly binds lipoprotein particles and apolipoproteins such as APOE, thereby influencing cholesterol and lipid metabolism in microglia. This lipid sensing function is crucial for processing myelin and other extracellular lipid debris, and loss‐of‐function mutations have been shown to lead to intracellular lipid accumulation that further exacerbates neurodegenerative changes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTREM2 undergoes proteolytic processing to release a soluble ectodomain (sTREM2) detectable in cerebrospinal fluid. Changes in sTREM2 levels have been observed in the early symptomatic phase of Alzheimer’s disease and correlate with markers of neuronal injury and tau pathology, suggesting that the soluble receptor may represent a sensitive biomarker of microglial activation and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond Alzheimer’s pathology, TREM2 functional deficits have implications in a range of neurological disorders. Its activity is important in the clearance of myelin debris in demyelinating conditions such as multiple sclerosis, and TREM2-dependent signaling is also crucial for osteoclast differentiation and bone remodeling—processes that, when disrupted, give rise to syndromes like Nasu–Hakola disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies have further implicated TREM2 in regulating tau pathology and downstream intracellular signaling. In experimental models of tauopathy, proper TREM2 function is necessary for microglial responses that limit tau-mediated neurodegeneration, while disease-associated variants result in impaired microglial activation and altered plaque dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTREM2 also appears to serve as a hub within a broader microglia gene network that coordinates immune responses, cytoskeletal reorganization, and chemotactic migration. Its central position in this network links not only innate immunity but also inflammatory signaling cascades that are shared among various neurodegenerative conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional insights from human cohort studies and cellular models have emphasized the complexity of TREM2 biology. Variations in noncoding regions and subtle changes in its expression have been linked to changes in APOE-related risk and inflammatory profiles, while studies in genetically engineered microglia demonstrate that loss of TREM2 not only compromises phagocytosis but also affects chemotaxis and survival. These observations point to a multifaceted regulatory role of TREM2 in neuroimmune homeostasis that is critical across species and disease contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Juha Paloneva, Tuula Manninen, Grant Christman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/342259"}], "href": "https://doi.org/10.1086/342259"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12080485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12080485"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Rita Guerreiro, Aleksandra Wojtas, Jose Bras, et al. 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