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Cited by 192Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

The DOI matches its Crossref record; 215 of the 215 references it cites were found in a registry or an index.

TREM2 dependent and independent functions of microglia in Alzheimer’s disease

Open access
Hou, Jinchao, Chen, Yun, Grajales-Reyes, Gary, Colonna, Marco·2022·Molecular Neurodegeneration
DOI 10.1186/s13024-022-00588-yPMC PMC9783481
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Abstract

Microglia are central players in brain innate immunity and have been the subject of extensive research in Alzheimer's disease (AD). In this review, we aim to summarize the genetic and functional discoveries that have advanced our understanding of microglia reactivity to AD pathology. Given the heightened AD risk posed by rare variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2), we will focus on the studies addressing the impact of this receptor on microglia responses to amyloid plaques, tauopathy and demyelination pathologies in mouse and human. Finally, we will discuss the implications of recent discoveries on microglia and TREM2 biology on potential therapeutic strategies for AD.

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Fig. 1 Microglial features in steady-state. In steady-state, microglia are maintained via paracrine colony-stimulating factor-1 receptor (CSF1R) signaling and via autocrine transforming growth factor-β (TGFβ) signaling. The two pathways endow a unique homeostatic feature of microglia, characterized by high expression levels of P2ry12, Cx3cr1, Tmem119, MerTK, Itgam and others. Microglia lineage-determining transcription factors PU.1, myocyte enhancer factor 2A (Mef2a), mothers against decapentaplegic homolog 3 (Smad3), transcription factors MafB (MafB), interferon regulatory factor 8 (Irf8), and spalt-like transcription factor 1 (Sall1) control microglia homeostasis. The features of homeostatic microglia make them well suited to the physiological functions, including neuronal trophic support via BDNF release, myelination via IGF-1 secretion, and synaptic pruning. Microglia remove excess synapses from postnatal or adult-born neuron via diverse ligand-receptor pathways including C3-CR3, PS-TREM2, Gas-MerTK, CX3CL1-CX3CR1, ADP-P2RY12, et al. OLs, oligodendrocytes; OPC, oligodendrocyte progenitor cell; IGF-1, insulin-like growth factor 1; BDNF, brain derived neurotrophic factor; CR3, complement receptor 3; TREM2, triggering receptor expressed on myeloid cells 2; MerTK, Mer tyrosine kinase; P2RY12, purinergic receptor P2Y; CX3CR1, C-X3-C motif chemokine receptor 1; C1q, complement component 1q; PS, phosphatidylserine; Gas6, growth arrest-specific 6; ADP, adenosine diphosphate; CX3CL1, C-X3-C motif chemokine ligand 1; TGFBR1/2, TGF-β receptor 1/2
Fig. 1 Microglial features in steady-state. In steady-state, microglia are maintained via paracrine colony-stimulating factor-1 receptor (CSF1R) signaling and via autocrine transforming growth factor-β (TGFβ) signaling. The two pathways endow a unique homeostatic feature of microglia, characterized by high expression levels of P2ry12, Cx3cr1, Tmem119, MerTK, Itgam and others. Microglia lineage-determining transcription factors PU.1, myocyte enhancer factor 2A (Mef2a), mothers against decapentaplegic homolog 3 (Smad3), transcription factors MafB (MafB), interferon regulatory factor 8 (Irf8), and spalt-like transcription factor 1 (Sall1) control microglia homeostasis. The features of homeostatic microglia make them well suited to the physiological functions, including neuronal trophic support via BDNF release, myelination via IGF-1 secretion, and synaptic pruning. Microglia remove excess synapses from postnatal or adult-born neuron via diverse ligand-receptor pathways including C3-CR3, PS-TREM2, Gas-MerTK, CX3CL1-CX3CR1, ADP-P2RY12, et al. OLs, oligodendrocytes; OPC, oligodendrocyte progenitor cell; IGF-1, insulin-like growth factor 1; BDNF, brain derived neurotrophic factor; CR3, complement receptor 3; TREM2, triggering receptor expressed on myeloid cells 2; MerTK, Mer tyrosine kinase; P2RY12, purinergic receptor P2Y; CX3CR1, C-X3-C motif chemokine receptor 1; C1q, complement component 1q; PS, phosphatidylserine; Gas6, growth arrest-specific 6; ADP, adenosine diphosphate; CX3CL1, C-X3-C motif chemokine ligand 1; TGFBR1/2, TGF-β receptor 1/2CC BY · PubMed Central
Fig. 2 Microglial features in Alzheimer’s disease (AD). a AD is pathologically characterized by extracellular beta-amyloid (Aβ) aggregates, intracellular tau neurofibrillary tangles (NFT) and neuronal cell death. b In the setting of AD, microglia act as the initial responders to brain damage and respond to various pathological hallmarks, including Aβ oligomer, tau and myelin debris, adopting DAM and IFN-responsive microglia features via pathways that are in part TREM2 or APOE-dependent. Both DAM and IFN-R microglia are characterized by downregulation of homeostatic genes (such as P2ry12). DAM upregulate various genes, such as Clec7a. IFN-R microglia feature a list of up-regulated genes, including Irf7 and Stat1. Transcriptional factors, such as Bhlhe40, Tfec and Atf3, are commonly induced in the reactive microglia through “TREM2-APOE” signaling. c In Aβ-bearing pathology, TREM2 and APOE collaboratively serve as a barrier to limit Aβ-induced neuronal toxicity by inducing microglial clustering. Lack of TREM2 or APOE results in a defect of DAM, and abundant Aβ42 and dystrophic neurites around filamentous plaques. d In tauopathy, TREM2 or APOE deficiency limits microgliosis and restrain neuronal loss in late-stage disease. DAM, disease-associated microglia; IFN-R, IFN-I-response
Fig. 2 Microglial features in Alzheimer’s disease (AD). a AD is pathologically characterized by extracellular beta-amyloid (Aβ) aggregates, intracellular tau neurofibrillary tangles (NFT) and neuronal cell death. b In the setting of AD, microglia act as the initial responders to brain damage and respond to various pathological hallmarks, including Aβ oligomer, tau and myelin debris, adopting DAM and IFN-responsive microglia features via pathways that are in part TREM2 or APOE-dependent. Both DAM and IFN-R microglia are characterized by downregulation of homeostatic genes (such as P2ry12). DAM upregulate various genes, such as Clec7a. IFN-R microglia feature a list of up-regulated genes, including Irf7 and Stat1. Transcriptional factors, such as Bhlhe40, Tfec and Atf3, are commonly induced in the reactive microglia through “TREM2-APOE” signaling. c In Aβ-bearing pathology, TREM2 and APOE collaboratively serve as a barrier to limit Aβ-induced neuronal toxicity by inducing microglial clustering. Lack of TREM2 or APOE results in a defect of DAM, and abundant Aβ42 and dystrophic neurites around filamentous plaques. d In tauopathy, TREM2 or APOE deficiency limits microgliosis and restrain neuronal loss in late-stage disease. DAM, disease-associated microglia; IFN-R, IFN-I-responseCC BY · PubMed Central
Fig. 3 Structural insights into TREM2 ligand recognition and the impact of LOF mutation. a Structural alignment of TREM2 CV (PDB: 5UD7) vs. TREM2 R47H (PDB: 5UD8). The top cartoon depiction shows the overall structure of TREM2 R47H (in beige) superposed with TREM2 CV (in grey). The β-strands and CDR loops of Ig-like domain of TREM2 were labeled from A to G and from CDR1 to CDR3, respectively. The red dashed arrows indicate the conformational change of CDR2 loop caused by R47H mutation. At the bottom, the left panel of the zoom-in image shows that R47 is involved in an interacting network with S65, N68 and R77 to stabilize regular TREM2 Ig folding of the C’’ strain and CDR2 loop in TREM2 CV. The right panel of the zoom-in image illustrates that H47 (in pink) forms a new aromatic π–π stacking with H67 (red dashed line), leading to a turning of H67 (red dashed arrow) from normal orientation (grey H67) and CDR2 conformation change (black dashed arrow). b The embedded phosphatidylserine (PS) binding pocket is created by two adjacent TREM2 molecules (TREM2 and TREM2’). The original structures of TREM2 are shown with electrostatic surface area and PS molecule is presented with sticks for better visualization (modified from PDB: 6B8O). Green indicates the surface of TREM2, and Cyan indicates the surface of TREM2’. Blue highlights indicate the NH groups and red highlights the CO groups of the protein. In the zoom-in image, blue sticks/surface show the hydrophilic residues interacting with PS head groups, and yellow sticks/surface illustrate the hydrophobic neck of the ligand binding pocket. c The structural model of PS binding to TREM2 dimer (modified from PDB: 6B8O). Highlighted sticks in the zoom-out panel show all the putative interactions and the physical distances between interacting atoms (dashed bar) in the PS binding sites. Dark green sticks show the residues from TREM2 interacting with the PS molecule; light cyan sticks show the residues from TREM2’ interacting with the PS molecule. Residues with apostrophe marks are from the second TREM2 molecule (TREM2’)
Fig. 3 Structural insights into TREM2 ligand recognition and the impact of LOF mutation. a Structural alignment of TREM2 CV (PDB: 5UD7) vs. TREM2 R47H (PDB: 5UD8). The top cartoon depiction shows the overall structure of TREM2 R47H (in beige) superposed with TREM2 CV (in grey). The β-strands and CDR loops of Ig-like domain of TREM2 were labeled from A to G and from CDR1 to CDR3, respectively. The red dashed arrows indicate the conformational change of CDR2 loop caused by R47H mutation. At the bottom, the left panel of the zoom-in image shows that R47 is involved in an interacting network with S65, N68 and R77 to stabilize regular TREM2 Ig folding of the C’’ strain and CDR2 loop in TREM2 CV. The right panel of the zoom-in image illustrates that H47 (in pink) forms a new aromatic π–π stacking with H67 (red dashed line), leading to a turning of H67 (red dashed arrow) from normal orientation (grey H67) and CDR2 conformation change (black dashed arrow). b The embedded phosphatidylserine (PS) binding pocket is created by two adjacent TREM2 molecules (TREM2 and TREM2’). The original structures of TREM2 are shown with electrostatic surface area and PS molecule is presented with sticks for better visualization (modified from PDB: 6B8O). Green indicates the surface of TREM2, and Cyan indicates the surface of TREM2’. Blue highlights indicate the NH groups and red highlights the CO groups of the protein. In the zoom-in image, blue sticks/surface show the hydrophilic residues interacting with PS head groups, and yellow sticks/surface illustrate the hydrophobic neck of the ligand binding pocket. c The structural model of PS binding to TREM2 dimer (modified from PDB: 6B8O). Highlighted sticks in the zoom-out panel show all the putative interactions and the physical distances between interacting atoms (dashed bar) in the PS binding sites. Dark green sticks show the residues from TREM2 interacting with the PS molecule; light cyan sticks show the residues from TREM2’ interacting with the PS molecule. Residues with apostrophe marks are from the second TREM2 molecule (TREM2’)CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Steixner-Kumar AA, Subramanian S, Möbius W, Göbbels S, Saher G et al: Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease. 2021. BioRixv. Available from https://www.biorxiv.org/content/biorxiv/early/2021/08/02/2021.07.31.454562.full.pdf.

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Metadata

Authors
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Colonna, Marco
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2022-12-23
Volume
17
Issue
1
Pages
84-84
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-022-00588-y
PMC
PMC9783481
OpenAlex
W4312179313
Cited by
191
References
214
Citations by year
2026: 49 · 2025: 61 · 2024: 58 · 2023: 23
FWCI
3.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (RF1 AG051485, R21 AG059176, RF1 AG059082)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
microglia, TREM2, Alzheimer's disease, amyloid plaques, tauopathy, demyelination, microglial activation, innate immunity, Alzheimer's disease therapeutics
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Immunity, Innate, Membrane Glycoproteins, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Mice

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