TREM2 triggers microglial density and age-related neuronal loss
Open accessAbstract
The microglial triggering receptor expressed on myeloid cells 2 (TREM2) signals via the activatory membrane adaptor molecule TYROBP. Genetic variants or mutations of TREM2 or TYROBP have been linked to inflammatory neurodegenerative diseases associated with aging. The typical aging process goes along with microglial changes and mild neuronal loss, but the exact contribution of TREM2 is still unclear. Aged TREM2 knock-out mice showed decreased age-related neuronal loss in the substantia nigra and the hippocampus. Transcriptomic analysis of the brains of 24 months old TREM2 knock-out mice revealed 211 differentially expressed genes mostly downregulated and associated with complement activation and oxidative stress response pathways. Consistently, 24 months old TREM2 knock-out mice showed lower transcription of microglial (Aif1 and Tmem119), oxidative stress markers (Inos, Cyba, and Cybb) and complement components (C1qa, C1qb, C1qc, C3, C4b, Itgam, and Itgb2), decreased microglial numbers and expression of the microglial activation marker Cd68, as well as accumulation of oxidized lipids. Cultured microglia of TREM2 knock-out mice showed reduced phagocytosis and oxidative burst. Thus, microglial TREM2 contributes to age-related microglial changes, phagocytic oxidative burst, and loss of neurons with possible detrimental effects during physiological aging.
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TREM2 deficiency results in lower transcription levels of IBA1 and a decrease in IBA1-positive microglia, visible at every timepoint tested and increasing with age.
“Consistent with these results, experiments investigating the deficiency of TREM2 detected lower transcription levels of IBA1 and a decrease in IBA1-positive microglia. This observation was visible at every timepoint tested and even increased with age [35].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [35]
Impaired or absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage.
“Recent important studies have also shown that impaired/absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage (37,61,84–87,95–99).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [87]
Other studies have not revealed obvious phenotypes in young Trem2 R47H expressing mice, or even Trem2 knockout mice, unless they are aged or bred to amyloid mouse models.
“Other studies have not revealed obvious phenotypes in young Trem2 R47H expressing mice, or even Trem2 knockout mice, unless they are aged or bred to amyloid mouse models (35,61,85–87).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [87]
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- Authors
- Linnartz‐Gerlach, B., Bodea, L., Klaus, C., Ginolhac, A., Halder, R., Sinkkonen, L., Walter, J., Colonna, M., & Neumann, H.
- Affiliations
- University of Bonn (DE)
- University of Luxembourg (LU)
- Washington University in St. Louis (US)
- Corresponding author
- Neumann, Harald
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2018-12-11
- Volume
- 67
- Issue
- 3
- Pages
- 539-550
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC6590266
- OpenAlex
- W2904803384
- Cited by
- 104
- References
- 40
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 11 · 2023: 14 · 2022: 13 · 2021: 23 · 2020: 13 · 2019: 7
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Glia (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (DFG‐ImmunoSensation‐EXC1023, DFG‐SFB704, DFG‐LI 2833/1‐1)
- Gemeinnützige Hertie-Stiftung
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- TREM2, TYROBP, microglia, aging, age-related neuronal loss, microglial density, complement activation, oxidative stress, phagocytosis, respiratory burst, substantia nigra, hippocampus, oxidized lipids, neurodegeneration
- MeSH terms
- Age Factors, Aging, Animals, Hippocampus, Membrane Glycoproteins, Neurons, Phagocytosis, Receptors, Immunologic, Substantia Nigra, Microglia, Mice, Knockout, Oxidative Stress, Mice
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