Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice
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Abstract
Introduction: Microglial TYROBP (DAP12) is a network hub and driver in sporadic late‐onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription is specifically increased in recruited microglia. Methods: Using a novel transgenic mouse overexpressing TYROBP in microglia, we observed a decrease of the amyloid burden and an increase of TAU phosphorylation stoichiometry when crossed with APP/PSEN1 or MAPT P301S mice, respectively. Characterization of these mice revealed Tyrobp ‐related modulation of apolipoprotein E ( Apoe ) transcription. We also showed that Tyrobp and Apoe mRNAs were increased in Trem2 ‐null microglia recruited around either amyloid beta deposits or a cortical stab injury. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. Conclusions: Our results provide evidence that TYROBP‐APOE signaling does not require TREM2 and could be an initiating step in establishment of the d isease‐ a ssociated m icroglia (DAM) phenotype.
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M7 shows high expression of activation marker Tyrobp.
“whereas M7 shows high expression of activation marker Tyrobp. 36 , 37 , 38”
From Loss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [38]
The Results (Figure 1) report increased Tyrobp expression in recruited microglia, supporting the expression part of the claim. Our copy does not identify an M7 population or show that M7 has high Tyrobp expression. The Results also distinguish recruitment from activation: Tyrobp mRNA was unchanged in activated resident microglia. (LLM, conf=0.82)
Experimental — accuracy not yet measuredManipulation of molecules involved in immune/microglial function in either direction may result in detrimental or exacerbated pathological outcomes.
“However, as we have previously seen in our studies modulating Tyrobp expression, manipulation of molecules involved in immune/microglial function in either direction may result in detrimental or exacerbated pathological outcomes.49,53,54,56”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [49]
TYROBP regulates APOE signaling independent of TREM2.
“TYROBP has also been shown to regulate APOE signaling independent of TREM2.49”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [49]
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Haure-Mirande, J.-V., Audrain, M., Ehrlich, M. E., & Gandy, S. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00552-w · Cited by 159 · see citing works
Self-citationCastranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74 · see citing works
“49, 53,54,56 A similar interpretation could be developed from the studies of Trem2 deficiency, as differences were dependent on early versus later disease stages.”
Self-citationLoss of <i>Inpp5d</i> has disease‐relevant and sex‐specific effects on glial transcriptomes
Dabin, L. C., Kersey, H., Kim, B., Acri, D. J., Sharify, D., Lee‐Gosselin, A., Lasagna‐Reeves, C. A., Oblak, A. L., Lamb, B. T., & Kim, J. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13901 · Cited by 10 · see citing works
“Two 36–38 M8 shows high expression of Lpl , a gene recently implicated in myelin-scavenging activated microlia.”
- Authors
- Audrain, M., Haure‐Mirande, J., Mleczko, J., Wang, M., Griffin, J. K., St George‐Hyslop, P. H., Fraser, P., Zhang, B., Gandy, S., & Ehrlich, M. E.
- Affiliations
- Department of Neurology Icahn School of Medicine at Mount Sinai New York New York USA
- Icahn School of Medicine at Mount Sinai (US)
- University of Toronto (CA)
- Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto ON Canada
- James J. Peters VA Medical Center (US)
- Corresponding author
- Gandy, Sam
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2020-12-12
- Volume
- 17
- Issue
- 2
- Pages
- 149-163
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC7938663
- OpenAlex
- W3112334124
- Cited by
- 65
- References
- 21
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 17 · 2023: 8 · 2022: 12 · 2021: 4 · 2020: 1
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (U01 AG046170, R01 AG057907)
- 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
- TYROBP, DAP12
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Humans, Membrane Glycoproteins, Mice, Transgenic, Phosphorylation, Receptors, Immunologic, Signal Transduction, Amyloid beta-Protein Precursor, tau Proteins, Microglia, Mice, Knockout, Adaptor Proteins, Signal Transducing, Mice, Presenilin-1
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