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

The DOI matches its Crossref record; 166 of the 166 references it cites were found in a registry or an index.

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 kinases
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)
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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Metadata

Authors
Gratuze, M., Leyns, C. E. G., & Holtzman, D. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Holtzman, David M.
ORCID
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
Licence
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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