| 2015 |
TREM2 directly senses a broad array of anionic and zwitterionic lipids associated with fibrillar Aβ and damaged-neuron membranes, triggering intracellular protein tyrosine phosphorylation; the R47H mutation impairs this lipid detection. In the 5XFAD mouse model, TREM2 deficiency and haploinsufficiency augment Aβ accumulation due to failure of microglia to cluster around plaques and increased microglial apoptosis. |
Lipid-binding assays, 5XFAD mouse model (knockout and haploinsufficient), microglial survival and clustering assays, intracellular phosphorylation readouts |
Cell |
High |
25728668
|
| 2016 |
TREM2 binds apolipoproteins (including APOE and CLU/APOJ) and lipoprotein particles (including LDL), identified by unbiased protein microarray screen. Disease-associated TREM2 mutations abolish or reduce this binding. TREM2 overexpression enhances uptake of LDL, CLU, and APOE; Trem2 knockout microglia show reduced internalization. Aβ-lipoprotein complexes are taken up by microglia in a TREM2-dependent manner, and uptake is reduced in macrophages from human TREM2-AD-variant carriers. |
Protein microarray screen, Co-IP/binding assays, overexpression and knockout cell assays, human macrophage uptake assay |
Neuron |
High |
27477018
|
| 2018 |
TREM2 directly binds Aβ oligomers with nanomolar affinity; AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglia and mouse brain. Aβ-induced microglial responses (depolarization, K+ inward current, cytokine expression/secretion, migration, proliferation, apoptosis, morphological changes) are dependent on TREM2. Aβ enhances TREM2 interaction with its signaling adaptor DAP12, regulating downstream phosphorylation of SYK and GSK3β. |
Direct binding assay (nanomolar affinity measurement), primary microglial culture KO, mouse brain KO, Co-IP (TREM2–DAP12), phosphorylation assays (SYK, GSK3β), electrophysiology |
Neuron |
High |
29518356
|
| 2014 |
TREM2 undergoes ectodomain shedding by ADAM proteases (α-secretases). FTD/FTD-like syndrome-associated missense mutations reduce TREM2 maturation, abolish ADAM-mediated shedding, and impair phagocytic activity of TREM2-expressing cells. Reduced shedding results in virtual absence of soluble TREM2 in CSF and plasma. |
Cell-based maturation and shedding assays, phagocytosis assays, CSF/plasma protein measurement in patients, protease inhibitor experiments |
Science translational medicine |
High |
24990881
|
| 2017 |
TREM2 sustains microglial metabolic fitness by enabling mTOR signaling. TREM2-deficient microglia in AD mice and in AD patients carrying TREM2 risk variants display abundant autophagic vesicles linked to defective mTOR signaling, reduced ATP levels, and impaired biosynthetic pathways. Metabolic rescue via cyclocreatine (ATP analog) restores microglial clustering around plaques and decreases neuronal dystrophy in TREM2-deficient AD mice. |
Combined metabolomics and RNA-seq, mouse models (TREM2-deficient with amyloid pathology), in vitro rescue experiments, dietary cyclocreatine intervention, autophagic vesicle quantification |
Cell |
High |
28802038
|
| 2017 |
TREM2 induces APOE signaling, mediating a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. Targeting the TREM2-APOE pathway restored homeostatic microglial signature in ALS and AD mouse models and prevented neuronal loss in an acute neurodegeneration model. |
Mouse models of ALS, MS, AD (genetic and pharmacological targeting), transcriptional profiling, apoptotic neuron phagocytosis assay |
Immunity |
High |
28930663
|
| 2019 |
CD33 acts upstream of TREM2 in modulating microglial pathology in Alzheimer's disease. CD33 knockout attenuates Aβ pathology and improves cognition in 5xFAD mice, effects abrogated by additional TREM2 knockout. TREM2 knockout exacerbates Aβ pathology, and this cannot be rescued by CD33 knockout. RNA-seq shows phagocytosis- and signaling-related genes upregulated in 5xFAD;CD33-/- microglia depend on TREM2 presence. |
Genetic epistasis (double knockout mouse models), RNA-seq of sorted microglia, behavioral testing, amyloid burden quantification |
Neuron |
High |
31301936
|
| 2019 |
In the absence of functional TREM2, amyloid plaque seeding is increased due to reduced microglial clustering around newly seeded plaques and reduced plaque-associated ApoE deposition. Microglia are identified as one source of plaque-associated ApoE by microglia depletion experiments. Longitudinal amyloid PET demonstrates accelerated early amyloidogenesis in Trem2 loss-of-function mutants. |
Mouse models, microglia depletion experiments, proteomics, longitudinal amyloid small-animal PET, human brain tissue from TREM2 variant carriers |
Nature neuroscience |
High |
30617257
|
| 2020 |
TREM2 is a key transcriptional regulator of cholesterol transport and metabolism under chronic phagocytic challenge. TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in cholesteryl ester (CE) accumulation. CE accumulation is also observed in APOE-deficient glial cells. This is replicated in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia and rescued by ACAT1 inhibitor and LXR agonist. |
Chronic demyelination mouse model, cell sorting with RNA-seq and lipidomics, TREM2-deficient murine macrophages, human iPSC-derived microglia, pharmacological rescue (ACAT1 inhibitor, LXR agonist) |
Neuron |
High |
31902528
|
| 2021 |
TREM2 interacts with TDP-43 protein, as demonstrated by mass spectrometry and surface plasmon resonance in vitro and in vivo, and in human ALS tissues. TREM2 deficiency impairs phagocytic clearance of pathological TDP-43 by microglia and enhances neuronal damage. Computationally identified regions within hTDP-43 interact with TREM2. |
Mass spectrometry, surface plasmon resonance (SPR), mouse viral/transgenic models, mass cytometry, human ALS tissue |
Nature neuroscience |
High |
34916658
|
| 2021 |
TREM2-dependent lipid droplet biogenesis is required for remyelination. Cholesterol esterification in microglia/macrophages is a necessary adaptive response to myelin debris uptake. TREM2-deficient mice cannot adapt to excess cholesterol, form fewer lipid droplets, and accumulate ER stress. Alleviating ER stress in TREM2-deficient mice restores lipid droplet biogenesis and resolves the innate immune response, enabling remyelination. |
Demyelinating injury mouse model, TREM2 KO mice, ER stress assays, lipid droplet quantification, pharmacological ER stress relief |
The Journal of experimental medicine |
High |
34424266
|
| 2019 |
Trem2 is a lipid-sensing receptor that controls lipid-associated macrophage (LAM) function in adipose tissue. Genetic ablation of Trem2 globally inhibits the downstream LAM transcriptional program, leading to adipocyte hypertrophy and systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. |
Single-cell RNA sequencing (mouse and human), Trem2 genetic ablation, metabolic phenotyping |
Cell |
High |
31257031
|
| 2020 |
TREM2-expressing regulatory myeloid (Mreg) cells with high Arginase 1 activity accumulate intratumorally. Genetic ablation of Trem2 inhibits accumulation of these Mreg cells, leading to decreased dysfunctional CD8+ T cells and reduced tumor growth. |
INs-seq (integrated scRNA-seq + intracellular protein activity profiling), Trem2 genetic ablation in mouse tumor models |
Cell |
High |
32783915
|
| 2020 |
The TREM2 transmembrane domain signals through the adaptor protein DAP12, which contains an ITAM motif. TREM2 ligation leads to Src family kinase activation, ITAM tyrosine phosphorylation, and recruitment of Syk and ZAP70 tyrosine kinases to initiate intracellular signaling cascade. |
Biochemical signaling assays, phosphorylation assays (referenced across multiple studies and review synthesis) |
Human immunology |
Medium |
23459077
|
| 2023 |
TREM2 mediates phagocytosis via Syk signaling in glioma-associated myeloid cells. TREM2+ myeloid cells display enhanced tumor uptake compared to TREM2- cells. TREM2 expression is positively associated with phagocytosis markers LYZ and CD163. |
In vivo phagocytosis tracking assay, in vitro phagocytosis assays, scRNA-seq of human gliomas, Syk inhibitor experiments, mouse glioma models |
Neuro-oncology |
Medium |
38237157
|
| 2021 |
TREM2 recognizes non-glycosylated mycolic acid (MA)-containing lipids from Mycobacterium cell walls via TREM2/DAP12-dependent but CARD9-independent signaling. This recruits iNOS-negative mycobacterium-permissive macrophages, opposing Mincle-FcRγ-CARD9-driven anti-mycobacterial immunity. TREM2 deletion enhances Mincle-induced macrophage activation and accelerates mycobacterial elimination, indicating TREM2-DAP12 counteracts anti-mycobacterial immunity. |
Macrophage activation assays, genetic KO (TREM2 and DAP12 KO mice), in vivo infection model, pathway epistasis (Mincle vs TREM2/DAP12) |
Nature communications |
High |
33863908
|
| 2020 |
TMEM59 (type I transmembrane protein) interacts with TREM2 (Co-IP). TREM2 overexpression promotes TMEM59 protein degradation, while Trem2-deficient microglia have elevated TMEM59 levels. Silencing TMEM59 rescues impaired survival, proliferation, migration, phagocytosis, and dysregulated autophagy and metabolism in Trem2-deficient microglia. |
Co-immunoprecipitation, overexpression and knockdown assays, Trem2-deficient microglia rescue experiments, autophagic flux assay |
Cell death & disease |
Medium |
32826884
|
| 2018 |
LILRB2, an inhibitory receptor bearing ITIM motifs, co-ligates with TREM2 on shared ligands (oligomeric Aβ and phosphatidylserine), leading to significant inhibition of TREM2 signaling. An antagonistic LILRB2 antibody (Ab29) prevents this inhibition, enhancing TREM2 signaling, microglial phagocytosis, migration, and cytokine responses in human iPSC-derived microglia and in vivo in 5XFAD mice. |
Human iPSC-derived microglia functional assays, antagonistic antibody blocking, in vivo 5XFAD stereotaxic grafting, phospho-signaling assays |
Molecular neurodegeneration |
Medium |
35717259
|
| 2020 |
Monoclonal antibody 4D9, targeting the stalk region epitope close to the TREM2 α-secretase cleavage site, reduces TREM2 shedding by ADAM10/17, stabilizes full-length TREM2 on the cell surface, and concomitantly activates phospho-SYK signaling. In vivo, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced the homeostatic marker in an AD mouse model. |
Antibody panel screening, shedding assays, phospho-SYK signaling assay, macrophage survival assay, myelin debris/Aβ phagocytosis in vitro, AD mouse model in vivo, CSF target engagement |
EMBO molecular medicine |
High |
32154671
|
| 2022 |
Trem2 deletion in microglia enhances tau trafficking to endosomal/pre-exosomal compartments after internalization (without affecting uptake), increases tau content in microglial exosomes, and elevates tau-seeding capacity of secreted exosomes. In vivo, Trem2 KO enhances tau spreading from medial entorhinal cortex to hippocampus, impairing synaptic function and memory. |
AAV-P301L tau injection model (MEC), microfluidic tau dispersion assay, exosome isolation and tau FRET reporter seeding assay, proteomics, exosome inhibitor experiments, mouse KO |
Molecular neurodegeneration |
High |
36056435
|
| 2023 |
Trem2 expression in microglia is required for maintaining normal neuronal bioenergetic profiles during postnatal development. In the absence of Trem2, CA1 (but not CA3) hippocampal pyramidal neurons display compromised energy metabolism, reduced mitochondrial mass, and abnormal organelle ultrastructure, accompanied by delayed neuronal maturation. |
Trem2 KO mouse model, single-cell/single-nucleus RNA sequencing, electron microscopy (mitochondrial ultrastructure), metabolic profiling of neurons by region |
Immunity |
High |
38159572
|
| 2023 |
TREM2 is required for efficient efferocytosis in macrophages. TREM2 deficiency reduces the ability of foamy macrophages to take up oxidized LDL. Mechanistically, TREM2-deficient macrophages fail to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. A genome-wide CRISPR screen identified Trem2 as associated with foamy macrophage specification. |
Genome-wide CRISPR screen, single-cell RNA sequencing trajectory analysis, myeloid-specific Trem2 KO mouse, oxLDL uptake assay, cholesterol efflux assay, atherosclerosis mouse model |
Nature cardiovascular research |
High |
38646596
|
| 2023 |
TREM2 promotes macrophage efferocytosis and survival of lipid-laden macrophages in atherosclerosis. TREM2 deficiency increased necrotic core formation. TREM2 agonism decreased necrotic core formation. TREM2 is essential for the efferocytosis capacities of macrophages. |
Hematopoietic/global TREM2 KO mouse models, TREM2 agonist treatment, atherosclerosis mouse models, efferocytosis assays |
Nature cardiovascular research |
High |
38974464
|
| 2023 |
TREM2 promotes cholesterol uptake and foam cell formation by upregulating scavenger receptor CD36 expression. Mechanistically, TREM2 inhibits phosphorylation of p38 MAPK and PPARγ, thereby increasing PPARγ nuclear transcriptional activity and promoting CD36 transcription. Trem2-/-/ApoE-/- mice show reduced atherosclerotic lesion size and lipid burden. |
ApoE-/- and Trem2-/-/ApoE-/- double-KO mouse models, TREM2 overexpression in SMCs and macrophages, oxLDL uptake assays, p38/PPARγ phosphorylation assays, CD36 transcription assay |
Cellular and molecular life sciences |
Medium |
37133566
|
| 2024 |
TREM2-expressing macrophages in cardiac ischemia (TREM2hi Mac1 subset) actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency impairs Mac1 self-renewal, leading to defective elimination of damaged mitochondria, excessive cardiac inflammation, exacerbated dysfunction, and decreased survival. |
scRNA-seq, fate mapping, Trem2 KO mouse model of sepsis, macrophage transfer experiments, mitochondria scavenging assays |
Nature metabolism |
High |
36635449
|
| 2024 |
In macrophages following efferocytosis, TREM2 decreases SLC25A53 transcription through the SYK-SMAD4 signaling pathway, impairing NAD+ transport into mitochondria and causing a breakpoint in the TCA cycle with increased itaconate production. Itaconate secreted by TREM2+ macrophages inhibits cardiomyocyte apoptosis and promotes fibroblast proliferation during MI repair. |
RNA-seq, protein interaction/molecular docking, targeted metabolomics (LC-MS), in vitro efferocytosis assays, macrophage-specific Trem2 KO mouse model of MI |
Cell death and differentiation |
Medium |
38182899
|
| 2023 |
TREM2+ macrophages suppress NK cell accumulation and cytolytic activity in lung cancer by modulating IL-18/IL-18BP decoy interactions and IL-15 production. Genetic deletion of Trem2 rescues NK cell accumulation and enables NK cell-mediated tumor regression. |
Murine lung adenocarcinoma model, Trem2 genetic deletion, cytokine profiling (IL-18, IL-18BP, IL-15), NK cell functional assays, TREM2 blockade synergy with NK cell-activating agent |
Nature immunology |
High |
37081148
|
| 2023 |
TREM2+ TAMs in hepatocellular carcinoma secrete less CXCL9 but more galectin-1 compared to TREM2- TAMs. Galectin-1 promotes PD-L1 overexpression in vessel endothelial cells, impeding CD8+ T cell recruitment. TREM2 deficiency increases CD8+ T cell infiltration and enhances anti-PD-L1 blockade efficacy. |
scRNA-seq, in vitro co-culture, TREM2-KO mouse models (orthotopic and spontaneous HCC), immunofluorescence, flow cytometry |
Journal of hepatology |
High |
36889359
|
| 2023 |
Soluble TREM2 (sTREM2) species (from both proteolytic shedding and alternatively spliced isoforms lacking transmembrane domain) inhibit long-term potentiation (LTP) in hippocampal brain slices, and this effect is abolished by the GABAA receptor antagonist picrotoxin. |
In vitro cleavage/secretion assays (HEK293T, HMC3), hippocampal LTP induction in brain slices, GABAA antagonist pharmacology, qPCR in AD patient post-mortem samples |
Genome medicine |
Medium |
36805764
|
| 2023 |
TREM2 is important for virus-induced IFNB induction through the cGAS-STING DNA-sensing pathway in microglia and for phagocytosis of HSV1-infected neurons. TREM2 augments STING signaling and activation of downstream targets TBK1 and IRF3. TREM2 depletion increased susceptibility to HSV1 infection in human microglia-neuron co-cultures and mouse brain. |
hiPSC-derived microglia with TREM2 depletion, IFNB induction assays, cGAS-STING/TBK1/IRF3 signaling assays, phagocytosis assay, mouse in vivo HSV1 infection |
Science advances |
Medium |
37595041
|
| 2018 |
TREM2 acts as a natural brake on TLR4-mediated proinflammatory signaling in hepatic macrophages and hepatic stellate cells. Trem2-deficient primary hepatic macrophages and stellate cells exhibit augmented TLR4-driven proinflammatory responses. Bone marrow transplantation experiments showed that both immune and resident cell TREM2 expression are required for full protection. |
Acute and chronic liver injury mouse models (Trem2 KO), primary hepatic macrophage isolation and TLR4 stimulation assays, bone marrow transplantation, ROS assays |
Gut |
Medium |
29374630
|
| 2023 |
TREM2 deficiency impairs glycolytic flux and oxidative metabolism in Schwann cells, triggering mitochondrial damage and autophagy via AMPK activation and impaired PI3K-AKT-mTOR signaling. This energy crisis in TREM2-deficient Schwann cells impairs cell proliferation and axonal regeneration, exacerbating neurological deficits in a mouse model of acute motor axonal neuropathy. |
TREM2 KO Schwann cell energy metabolism assays (glycolysis, oxidative phosphorylation), metabolomics, AMPK/PI3K-AKT-mTOR pathway analysis, sciatic nerve model |
Cell death & disease |
Medium |
38453910
|
| 2024 |
TREM2 functions as a key braking mechanism for the NLRP3/NF-κB/IL-1β inflammasome pathway in pancreatic macrophages, opposing microbial LPS as an activator of this pathway. TREM2 depletion orchestrates with LPS to trigger IL-1β upregulation and pathogenic inflammation, fueling PDAC development. IL-1β inhibition or microbiome ablation reverses the accelerated PDAC progression caused by TREM2 depletion. |
KPPC;Trem2-/- transgenic mouse model, scRNA-seq, IL-1β inhibition experiments, antibiotic-mediated microbiome ablation, pathway analysis (NLRP3/NF-κB/IL-1β) |
Gastroenterology |
Medium |
39956331
|
| 2024 |
Microglia gravitate toward amyloid plaques surrounded by externalized phosphatidylserine (ePtdSer) from dystrophic neurons via TREM2. TREM2-mediated phagocytosis of Aβ is accelerated by ePtdSer. TREM2 loss-of-function (frameshift in exon 2) reduces phagocytic activity toward ePtdSer-positive Aβ plaques. |
2D/3D/4D co-culture systems with CRISPR-engineered TREM2 loss-of-function brain organoids/microglia/assembloids, APPNL-G-F/MAPT double knock-in mice, APOE4 iPSC lines |
Advanced science |
Medium |
38981007
|
| 2023 |
TREM2-IGF1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects in ischemic stroke. IGF1 is a major downstream molecule of Trem2. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. |
Single-nuclei RNA sequencing, microglial depletion (PLX3397) + repopulation, Trem2/Igf1 overexpression, cyclocreatine metabolic rescue, ischemic stroke mouse model |
Advanced science |
Medium |
38151703
|
| 2023 |
Trem2 H157Y knock-in mutation increases TREM2 shedding, elevating soluble TREM2 levels in brain and serum. This enhances synaptic plasticity and, in the presence of amyloid pathology, accelerates Aβ clearance and reduces amyloid burden and dystrophic neurites. Targeted mass spectrometry shows higher ratios of soluble to full-length TREM2-H157Y versus WT TREM2. |
CRISPR/Cas9 knock-in mouse model, targeted mass spectrometry, biochemical assays, hippocampal electrophysiology (LTP), in vivo microdialysis, immunofluorescence, cortical bulk RNA-seq |
Molecular neurodegeneration |
High |
36721205
|