TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
Open accessAbstract
The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer's disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aβ) pathology and improved cognition in 5xFAD mice, both of which were abrogated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aβ pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by additional CD33 knockout. RNA-seq profiling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upregulated in 5xFAD;CD33-/- and downregulated in 5xFAD;TREM2-/- mice. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 includes regulation of the IL-1β/IL-1RN axis and a gene set in the "receptor activity chemokine" cluster. Our results should facilitate AD therapeutics targeting these receptors.
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Crosstalk between AD risk immune genes has been demonstrated, notably between Cd33 and Trem2.
“Crosstalk between AD risk immune genes has been recently demonstrated, notably between Cd33 and Trem2 [79].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [79]
Microglia from 5xFAD mice show canonical upregulation of disease-associated microglial markers (e.g. Cst7, Axl, Trem2, Apoe, Ctss) and loss of homeostatic markers (P2ry12, Tmem119).
“Microglia from these mice have been extensively characterized, revealing the canonical upregulation of disease-associated microglial markers (e.g. Cst7, Axl, Trem2, Apoe, Ctss) and loss of homoestatic markers (P2ry12, Tmem119) that reflect disease-related changes in form and function [12, 50, 51].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [50]
CD33 knockout decreases amyloid pathology and improves cognition in 5xFAD mice.
“CD33 KO results in decreased amyloid pathology and improved cognition in 5xFAD mice.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Griciuc et al., 2019
CD33 acts upstream of TREM2 based on knockout interaction studies.
“This is abrogated by additional TREM2 KO, however CD33 KO does not reciprocally abrogate effects of TREM2 KO, suggesting that CD33 acts upstream of TREM2 (Griciuc et al.,2019 .”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Griciuc et al., 2019
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 [86]
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 [86]
When genes that show substantial changes in transgenic mice associated with AD were tested, a number of aspects of gene expression were mimicked by anti-inflammatory IL-4 stimulation, particularly increased expression of genes associated with the neurodegenerative signature, including Igf1, Itgax, Clec7a and Arg1.
“Interestingly, when we tested expression of genes that show substantial changes in transgenic mice associated with AD (43,44) a number of aspects of gene expression were mimicked by anti-inflammatory IL-4 stimulation, particularly the increased expression of genes associated with the neurodegenerative signature, including Igf1, Itgax, Clec7a and Arg1 (58,59,61,84,86).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [86]
Recent studies identified transcriptional signatures in response to AD-associated pathology, neurodegeneration and apoptotic neurons that were in part dependent on Trem2 and included Igf1, Csf1, Itgax, Clec7a and Arg1, at least in mice.
“Indeed, a series of recent studies identified transcriptional signatures in response to AD-associated pathology, neurodegeneration and apoptotic neurons, which were in part dependent on Trem2 and included Igf1, Csf1, Itgax, Clec7a and Arg1, at least in mice (58,59,61,84,86).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [86]
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BackgroundSYK coordinates neuroprotective microglial responses in neurodegenerative disease
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“Indeed, a series of recent studies identified transcriptional signatures in response to AD-associated pathology, neurodegeneration and apoptotic neurons, which were in part dependent on Trem2 and included Igf1, Csf1, Itgax, Clec7a and Arg1, at least in mice (58,59,61,84,86).”
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BackgroundThe role of the immune system in Alzheimer’s disease
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The relationship of soluble TREM2 to other biomarkers of sporadic Alzheimer’s disease
Park, S., Lee, E.-H., Kim, H., Jo, S., Lee, S., Seo, S. W., Park, H.-H., Koh, S., & Lee, J. (2021) · Scientific Reports · doi:10.1038/s41598-021-92101-6 · Cited by 48 · see citing works
Key role of the CCR2-CCL2 axis in disease modification in a mouse model of tauopathy
Ben-Yehuda, H., Arad, M., Ramos, J. M. P., Sharon, E., Castellani, G., Ferrera, S., Cahalon, L., Colaiuta, S. P., Salame, T., & Schwartz, M. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00458-z · Cited by 46 · see citing works
- Authors
- Griciuc, A., Patel, S., Federico, A. N., Choi, S. H., Innes, B. J., Oram, M. K., Cereghetti, G., McGinty, D., Anselmo, A., Sadreyev, R. I., Hickman, S. E., El Khoury, J., Colonna, M., & Tanzi, R. E.
- Affiliations
- Harvard University (US)
- Washington University in St. Louis (US)
- Corresponding author
- Tanzi, Rudolph E.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2019-09
- Volume
- 103
- Issue
- 5
- Pages
- 820-835.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6728215
- OpenAlex
- W2961845320
- Cited by
- 378
- References
- 59
- Citations by year
- 2026: 36 · 2025: 63 · 2024: 54 · 2023: 49 · 2022: 65 · 2021: 59 · 2020: 42 · 2019: 8 · 2012: 1
- FWCI
- 19.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, CD33, Alzheimer's disease, microglia, amyloid-beta pathology, 5xFAD mice, microglial receptors, phagocytosis, microglial gene expression, neurodegeneration, cognitive impairment, receptor cross-talk
- MeSH terms
- Acute-Phase Reaction, Alzheimer Disease, Animals, Brain, Cognition, Disease Models, Animal, Gene Expression Regulation, Membrane Glycoproteins, Phagocytosis, Receptors, Immunologic, Interleukin-6, Interleukin-8, Amyloid beta-Peptides, Microglia, Mice, Knockout, Mice, Plaque, Amyloid, Sialic Acid Binding Ig-like Lectin 3
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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