ArticleNeuron2018
Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models.
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Article in Neuron, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 233 papers, 3 of them syntheses that pooled it.
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233citing papers in PubMed, 3 pooled it
18.2field-weighted citation impact, top 1% of its field
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Who cites it
233 citing papers in PubMed, 3 syntheses or guidelines pooled it, 416 citations in OpenAlex.
- Gain-of-function Modulation of TREM2 and its Impact on Amyloid-β and Tau Pathologies in Alzheimer's Disease: A Systematic Review and Meta-analysis of Animal Studies.Molecular neurobiology · 2026Pooled it
- The Amyloid-β Pathway in Alzheimer's Disease.Molecular psychiatry · 2021Pooled it
- Targeting TREM2 for Parkinson's Disease: Where to Go?Frontiers in immunology · 2021Pooled it
- The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial.Nature medicine · 2026Trial
- Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.Alzheimer's research & therapy · 2024Trial
- Predicting and finding geroprotective compounds through modulating conserved longevity-associated aging modules.Science advances · 2026Article
- Small-molecule TREM2 agonists: From artificial intelligence driven discovery to therapeutic application in Alzheimer's disease.Neural regeneration research · 2026Article
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- TMEM59 regulates microglial Aβ phagocytosis in a TREM2-dependent manner and acts as a potential therapeutic target for Aβ amyloidosis.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Increased plasma soluble TREM2 levels in non-Alzheimer's dementia.Acta neurologica Belgica · 2026Article
- The microglial TREM2 receptor programs hippocampal development in a mouse model of childhood deprivation.Brain, behavior, and immunity · 2026Article
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.Molecules (Basel, Switzerland) · 2026Review
- The role of DAP12 in immune-related inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- CD33 Isoform Splicing Dysregulation: A Molecular Determinant of Microglial Dysfunction in Alzheimer's Disease Pathology.Molecular neurobiology · 2026Review
- Immune signaling and function in neurodegeneration.The Journal of clinical investigation · 2026Review
- Advances in hiPSC-Derived Brain Organoids as a Model to Study Neuroinflammation in Alzheimer's Disease.Journal of neurochemistry · 2026Review
- Deficiency of Tissue Nonspecific Alkaline Phosphatase Dysregulates Microglial Morphology and Function in a Mouse Model of Infantile Hypophosphatasia.Journal of neurochemistry · 2026Article
- Synthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases.Cell reports. Medicine · 2026Article
173 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
C Y Daniel LeeCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Anthony DaggettCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Xiaofeng GuCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Lu-Lin JiangNeuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Peter LangfelderCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
Xiaoguang LiNeuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Nan WangCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Yingjun ZhaoNeuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Chang Sin ParkCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Yonatan CooperCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Isabella FerandoDepartment of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Istvan ModyBrain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Giovanni CoppolaCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Huaxi XuNeuroscience and Aging Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
X William YangCenter for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: xwyang@mednet.ucla.edu.
University of California, Los Angeles · USSanford Burnham Prebys Medical Discovery Institute · USDiscovery Institute · US
Funding
UCLA-Caltech Medical Scientist Training ProgramT32GM008042 · NIGMS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI AJIJOLA, OLUJIMI A, DAWSON, DAVID WAYNE · 1985 to 2023
$29.9MIntegrative Center for Neurogenetics and Neurogenomics - OverallP30NS062691 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI COPPOLA, GIOVANNI · 2009 to 2018
$7.4MMolecular pathobiology of soluble TREM2 in Alzheimer's disease.RF1AG056130 · NIA · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI HUANG, TIMOTHY YIKAI, ZHAO, NA · 2017 to 2023
$6.8MRegulation of Protein Trafficking in NeurodegenerationR01NS046673 · NINDS · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI XU, HUAXI · 2003 to 2018
$5.8MENDOGENOUS GABAERGIC ACTIVITY IN THE MAMMALIAN BRAINR01NS030549 · NINDS · UNIVERSITY OF TEXAS SW MED CTR/DALLAS · PI MODY, ISTVAN · 1992 to 2018
$4.5MBAC Transgenic Mouse Models of TREM2 to Study Neuroprotective Mechanisms in ADRF1AG056114 · NIA · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI YANG, XIANGDONG WILLIAM · 2017 to 2017
$4.1MThe Role of Appoptosin in Alzheimer's Disease and Other TauopathiesR01AG038710 · NIA · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI XU, HUAXI · 2011 to 2019
$3.9MIdentifying genes in Beta-Amyloid ProductionR01AG021173 · NIA · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI XU, HUAXI · 2004 to 2015
$3.3MCharacterizing neuroprotective roles for SNX27 signaling pathways in AD and DSRF1AG044420 · NIA · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI HUANG, TIMOTHY YIKAI · 2018 to 2018
$2.4MTraining Grant in Neurobehavioral GeneticsT32MH073526 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI BEARDEN, CARRIE E, GESCHWIND, DANIEL H · 2006 to 2020
$2.4MNovel Genetic Strategy for Sparse Labeling and Manipulation of Mammalian NeuronsU01MH106008 · NIMH · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI YANG, XIANGDONG WILLIAM · 2014 to 2016
$2.0MRoles of SN27 in regulating glutamate receptors during neurodegenerationR01AG044420 · NIA · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI XU, HUAXI · 2013 to 2017
$2.0MNIA NIH HHS R01 AG021173NIA NIH HHS R01 AG038710NIA NIH HHS R01 AG044420NIA NIH HHS R21 AG048519NIA NIH HHS RF1 AG044420NIA NIH HHS RF1 AG056114NIA NIH HHS RF1 AG056130NIMH NIH HHS T32 MH073526NIMH NIH HHS U01 MH106008NINDS NIH HHS P30 NS062691NINDS NIH HHS R01 NS030549NINDS NIH HHS R01 NS046673NINDS NIH HHS R01 NS074312NINDS NIH HHS R01 NS084298
Abstract
Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.
Indexed as
Disease Models, AnimalPhenotypeAlzheimer DiseaseAnimalsAnimals, NewbornCells, CulturedCellular Reprogramming TechniquesFemaleGene DosageHumansMaleMembrane GlycoproteinsMemoryMiceMice, Inbred C57BLMice, TransgenicMembrane GlycoproteinsReceptors, ImmunologicTrem2 protein, mouseAlzheimer’s diseaseamyloid plaqueBACgene dosagemicrogliamouseneuroinflammationreprogrammingRNA-sequencingTREM2
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