Cited by 496Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

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New insights into the role of TREM2 in Alzheimer’s disease

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Gratuze, Maud, Leyns, Cheryl E. G., Holtzman, David M.·2018·Molecular Neurodegeneration

DOI 10.1186/s13024-018-0298-9PMC PMC6302500

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Abstract

Alzheimer's disease (AD) is the leading cause of dementia. The two histopathological markers of AD are amyloid plaques composed of the amyloid-β (Aβ) peptide, and neurofibrillary tangles of aggregated, abnormally hyperphosphorylated tau protein. The majority of AD cases are late-onset, after the age of 65, where a clear cause is still unknown. However, there are likely different multifactorial contributors including age, enviornment, biology and genetics which can increase risk for the disease. Genetic predisposition is considerable, with heritability estimates of 60-80%. Genetic factors such as rare variants of TREM2 (triggering receptor expressed on myeloid cells-2) strongly increase the risk of developing AD, confirming the role of microglia in AD pathogenesis. In the last 5 years, several studies have dissected the mechanisms by which TREM2, as well as its rare variants affect amyloid and tau pathologies and their consequences in both animal models and in human studies. In this review, we summarize increases in our understanding of the involvement of TREM2 and microglia in AD development that may open new therapeutic strategies targeting the immune system to influence AD pathogenesis.

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Fig. 1 TREM2 ligands, signaling and functions. Ligands binding to TREM2 induce the association of TREM2 to DAP12 through an electrostatic interaction between a conserved positively-charged lysine in TREM2 (aa186) and a negatively- charged aspartic acid residue in DAP12, generating tyrosine phosphorylation of DAP12 within its immunoreceptor tyrosine-based activation motifs (ITAMS) by Src family kinasesCC BY · PubMed Central

Fig. 2 Schematic summary of the role of TREM2 and its variants in AD. a. Functional TREM2 has been suggested to allow microglia activation (by amyloid and NFTs for example), promote microglia clustering around plaques, amyloid uptake (early stage of the disease) and plaque compaction through binding to plaque-associated ApoE or directly to oligomeric Aβ. b. AD-associated TREM2 variants resulting in TREM2 partial loss-of-function abolished microglia clustering around plaque and phagocytic activity. These changes could be caused by a blockage of microglia in homeostatic stages because of less plaque-associated ApoE or other reasons. The consequences are filamentous plaques associate with increased dystrophic neurites and a possible increase of tau pathology (in early stages)CC BY · PubMed Central

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The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E
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Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2
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TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy
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Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation
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ApoE facilitates the microglial response to amyloid plaque pathology
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Structure and Function of Syk Protein-Tyrosine Kinase
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Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond
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Pattern Recognition by TREM-2: Binding of Anionic Ligands
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A Genome-wide Gene-Expression Analysis and Database in Transgenic Mice during Development of Amyloid or Tau Pathology
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Efficient colonic mucosal wound repair requires Trem2 signaling
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Blockade of TREM‐2 exacerbates experimental autoimmune encephalomyelitis
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TREM2 Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis
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Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals
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The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease
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Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis
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TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria
N’Diaye, E.-N., Branda, C., Branda, S. S., Nevarez, L., Colonna, M., Lowell, C. A., Hamerman, J. A., & Seaman, W. E. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200808080 · Cited by 243
Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody
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Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms
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Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy
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MRI and CSF studies in the early diagnosis of Alzheimer's disease
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Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2)
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TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy
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TREM-2 promotes macrophage survival and lung disease after respiratory viral infection
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The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease
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Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia
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TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance
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The structural basis for intramembrane assembly of an activating immunoreceptor complex
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Insights into TREM2 biology by network analysis of human brain gene expression data
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TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice
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The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44
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The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans
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Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia
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Specific lipid recognition is a general feature of CD300 and TREM molecules
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TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain
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TREM2 is associated with the risk of Alzheimer's disease in Spanish population
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TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function
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TREM2 R47H Variant as a Risk Factor for Early-Onset Alzheimer's Disease
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Genetics ignite focus on microglial inflammation in Alzheimer’s disease
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Accumulation of tau induced in neurites by microglial proinflammatory mediators
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TREM 2 Protein Expression Changes Correlate with Alzheimer's Disease Neurodegenerative Pathologies in Post‐Mortem Temporal Cortices
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Nuclear Receptors License Phagocytosis by Trem2+Myeloid Cells in Mouse Models of Alzheimer's Disease
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TREM2 is associated with increased risk for Alzheimer’s disease in African Americans
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The surface‐exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor
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Nasu–Hakola Disease (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy—PLOSL): A Dementia Associated with Bone Cystic Lesions. From Clinical to Genetic and Molecular Aspects
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microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration
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R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study
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Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer’s Disease
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DAP12 stabilizes the C-terminal fragment of the triggering receptor expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-inflammatory response
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R47H TREM2 variant increases risk of typical early‐onset Alzheimer's disease but not of prion or frontotemporal dementia
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Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia
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Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS
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SnapShot: genetics of Alzheimer's disease.
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Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice
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Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation
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Neuroprotective Effect of TREM-2 in Aging and Alzheimer’s Disease Model
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Increased Expression of TREM2 in Peripheral Blood of Alzheimer's Disease Patients
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The triggering receptor expressed on myeloid cells 2 ( TREM2 ) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia
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TREM2 upregulation correlates with 5-hydroxymethycytosine enrichment in Alzheimer’s disease hippocampus
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Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury
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The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway
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Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update
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Convergent Genetic and Expression Datasets Highlight TREM2 in Parkinson’s Disease Susceptibility
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Triggering receptor expressed on myeloid cells‐2 fine‐tunes inflammatory responses in murine Gram‐negative sepsis
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Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer’s disease brains
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Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer's disease in Han Chinese individuals
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Immunohistochemical characterization of microglia in Nasu‐Hakola disease brains
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TREM-2 Promotes Host Resistance Against Pseudomonas aeruginosa Infection by Suppressing Corneal Inflammation via a PI3K/Akt Signaling Pathway
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Investigation of TREM2, PLD3, and UNC5C variants in patients with Alzheimer's disease from mainland China
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TREM2 Ameliorates Neuronal Tau Pathology Through Suppression of Microglial Inflammatory Response
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Increasing CSF phospho-tau levels during cognitive decline and progression to dementia
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Increased expression of TREM 2 in peripheral cells from mild cognitive impairment patients who progress into Alzheimer's disease
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Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide
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Assessment of the Genetic Architecture of Alzheimer’s Disease Risk in Rate of Memory Decline
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Assessment of TREM2 rs75932628 association with Alzheimer's disease in a population-based sample: the Cache County Study
Murcia, J. D. G., Schmutz, C., Munger, C., Perkes, A. D., Gustin, A. J., Peterson, M., Ebbert, M., Norton, M. C., Tschanz, J. T., Munger, R. G., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.06.004 · Cited by 55
TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection
Gonçalves, L. A., Rodrigues-Duarte, L., Rodo, J., de Moraes, L. V., Marques, I., & Penha‐Gonçalves, C. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306873110 · Cited by 55
More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk
Rosenthal, S. L., Bamne, M. N., Wang, X., Berman, S., Snitz, B. E., Klunk, W. E., Sweet, R. A., Demirci, F. Y., López, O. L., & Kamboh, M. I. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.04.012 · Cited by 54
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Authors: Gratuze, M., Leyns, C. E. G., & Holtzman, D. M.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Holtzman, David M.
ORCID: Gratuze, Maud
Leyns, Cheryl E. G.
Holtzman, David M.
Venue: Molecular Neurodegeneration
Publisher: Springer Science and Business Media LLC
Published: 2018-12
Volume: 13
Issue: 1
Pages: 66-66
ISSN: 1750-1326 (ISSN-L)
DOI: 10.1186/s13024-018-0298-9
PMC: PMC6302500
OpenAlex: W2905219483
Cited by: 489
References: 166
Citations by year: 2026: 40 · 2025: 59 · 2024: 83 · 2023: 63 · 2022: 84 · 2021: 86 · 2020: 52 · 2019: 22
FWCI: 3.80
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (tdm)
Locations: Molecular Neurodegeneration (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
HAL (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: Edward N. and Della L. Thome Memorial Foundation (none)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: TREM2, Alzheimer's disease, microglia, amyloid plaques, amyloid-beta, tau pathology, genetic risk variants, late-onset Alzheimer's disease, neuroinflammation, therapeutic target, immune system
MeSH terms: Alzheimer Disease, Animals, Disease Models, Animal, Humans, Membrane Glycoproteins, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Plaque, Amyloid

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New insights into the role of TREM2 in Alzheimer’s disease

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