Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
Open accessAbstract
Background: Alzheimer’s Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance of APOE ε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major genetic risk factors for AD. Recent studies showed that APOE binds to TREM2, thus raising the possibility of an APOE-TREM2 interaction that can modulate AD pathology. Methods: The aim of this study was to investigate this interaction using complex AD model mice - a crossbreed of Trem2 ko and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms (APP/E3 and APP/E4 respectively), and their WT littermates (E3 and E4), and evaluate cognition, steady-state amyloid load, plaque compaction, plaque growth rate, glial response, and brain transcriptome. Results: In both, APP/E3 and APP/E4 mice, Trem2 deletion reduced plaque compaction but did not significantly affect steady-state plaque load. Importantly, the lack of TREM2 increased plaque growth that negatively correlated to the diminished microglia barrier, an effect most pronounced at earlier stages of amyloid deposition. We also found that Trem2 deficiency significantly decreased plaque-associated APOE protein in APP/E4 but not in APP/E3 mice in agreement with RNA-seq data. Interestingly, we observed a significant decrease of Apoe mRNA expression in plaque-associated microglia of APP/E4/Trem2 ko vs APP/E4 mice. The absence of TREM2, worsened cognitive performance in APP transgenic mice but not their WT littermates. Gene expression analysis identified Trem2 signature - a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all genotypes including APP and WT littermates. Furthermore, we identified sets of genes that were affected in TREM2- and APOE isoform-dependent manner. Among them were Clec7a and Csf1r upregulated in APP/E4 vs APP/E3 mice, a result further validated by in situ hybridization analysis. In contrast, Tyrobp and several genes involved in the C1Q complement cascade had a higher expression level in APP/E3 versus their APP/E4 counterparts. Conclusions: Our data demonstrate that lack of Trem2 differentially impacts the phenotype and brain transcriptome of APP mice expressing human APOE isoforms. The changes probably reflect the different effect of APOE isoforms on amyloid deposition.
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CLEC7A is a disease-associated microglia gene that increases after TBI in mice, in a mouse model of Alzheimer's disease, and in aged microglia associated with neurodegenerative disease.
“CLEC7A (FC = 2.02, p = 0.02) is a disease-associated microglia gene which has been shown to increase after TBI in mice [19], in a mouse model of AD [38, 56], and in aged microglia associated with neurodegenerative disease [135].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [38]
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- Authors
- Fitz, N. F., Wolfe, C. M., Playso, B. E., Biedrzycki, R. J., Lu, Y., Nam, K. N., Lefterov, I., & Koldamova, R.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Lefterov, Iliya
- Koldamova, Radosveta
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2020-07-23
- Volume
- 15
- Issue
- 1
- Pages
- 41-41
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC7379780
- OpenAlex
- W3044901278
- Cited by
- 68
- References
- 65
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 11 · 2023: 10 · 2022: 14 · 2021: 13 · 2020: 3
- FWCI
- 6.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (AG056371, AG066198, AG057565)
- Alzheimer's Association (AARF-16-443213)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, APOE ε4, APOE3, Alzheimer's disease, amyloid plaques, microglia, plaque progression, cognitive impairment, brain transcriptome, Dectin-1, CSF1R, TYROBP, immune response genes
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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