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TREM2 and the neuroimmunology of Alzheimer's disease
Open accessAbstract
Late-onset Alzheimer's disease (AD) is a sporadic disorder with increasing prevalence in aging. The ɛ4 allele of Apolipoprotein E(ApoEɛ4) was the only known major risk factor for late onset AD. Recently, two groups of investigators independently identified variants of the TREM2 gene, encoding triggering receptor expressed on myeloid cells 2 as causing increased susceptibility to late onset AD with an odds ratio similar to that of ApoEɛ4. TREM2 is a receptor expressed on innate immune cells. Using a novel technology called Direct RNA Sequencing wedetermined the quantitative transcriptome of microglia, the principal innate neuroimmune cells and confirmed that TREM2 is a major microglia-specific gene in the central nervous system. Over the past several years we have shown that microglia play a dichotomous role in AD. Microglia can be protective and promote phagocytosis, degradation and ultimately clearance of Aβ, the pathogenic protein deposited in the brains of Alzheimer's patients. However, with disease progression, microglia become dysfunctional, release neurotoxins, lose their ability to clear Aβ and produce pro-inflammatory cytokines that promote Aβ production and accumulation. TREM2 has been shown to regulate the phagocytic ability of myeloid cells and their inflammatory response. Here we propose that the mechanism(s) by which TREM2 variants cause Alzheimer's disease are via down regulation of the Aβ phagocytic ability of microglia and by dysregulation of the pro-inflammatory response of these cells. Based on our discussion we propose that TREM2 is a potential therapeutic target for stopping ordelaying progression of AD.
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“In addition, two groups of investigators independently identified variants of the microglial TREM2 gene that increase susceptibility to LOAD with an odds ratio similar to that of APOEε4 [56–58].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [58]
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Metadata
- Authors
- Hickman, S. E., & El Khoury, J.
- Affiliations
- Harvard University (US)
- ORCID
- Hickman, Suzanne E.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 88
- Issue
- 4
- Pages
- 495-498
- ISSN
- 0006-2952 (ISSN-L)
- PMC
- PMC3972304
- OpenAlex
- W2070847731
- Cited by
- 221
- References
- 48
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 18 · 2023: 10 · 2022: 20 · 2021: 14 · 2020: 14 · 2019: 19 · 2018: 25 · 2017: 28 · 2016: 19 · 2015: 16 · 2014: 13
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NINDS (NS059005)
- NIA to JEK (AG032349)
- 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, late-onset Alzheimer's disease, microglia, neuroimmunology, amyloid-beta clearance, phagocytosis, innate immunity, APOE ε4, genetic risk factors, inflammatory cytokines, therapeutic target
- MeSH terms
- Alzheimer Disease, Humans, Membrane Glycoproteins, Phagocytes, Receptors, Immunologic, Risk Factors, Amyloid beta-Peptides, Microglia, Genetic Predisposition to Disease
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