Sustained Trem2 stabilization accelerates microglia heterogeneity and Aβ pathology in a mouse model of Alzheimer’s disease
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Abstract
TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer's disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. Here, we generate a transgenic mouse model of reduced Trem2 shedding (Trem2-Ile-Pro-Asp [IPD]) through amino-acid substitution of an ADAM-protease recognition site. We show that Trem2-IPD mice display increased Trem2 cell-surface-receptor load, survival, and function in myeloid cells. Using single-cell transcriptomic profiling of mouse cortex, we show that sustained Trem2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Aβ pathology in a mouse model of Alzheimer's disease. Our data indicate that reduction of Trem2 proteolytic cleavage aggravates neuroinflammation during the course of Alzheimer's disease pathology, suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.
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Prolonged TREM2 activation by inhibiting its proteolytic cleavage in another Alzheimer's disease mouse model increased plaque deposition and promoted neuroinflammation at an early stage of amyloidogenesis.
“In line with this, prolonged TREM2 activation by inhibiting its proteolytic cleavage in another AD mouse model increased plaque deposition and promoted neuroinflammation at an early stage of amyloidogenesis [39].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [39]
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Self-citation
- Authors
- Dhandapani, R., Neri, M., Bernhard, M., Brzak, I., Schweizer, T., Rudin, S., Joller, S., Berth, R., Kernen, J., Neuhaus, A., Waldt, A., Cuttat, R., Naumann, U., Keller, C. G., Roma, G., Feuerbach, D., Shimshek, D. R., Neumann, U., Gasparini, F., & Galimberti, I.
- Affiliations
- Novartis Institutes for BioMedical Research (CH)
- Novartis (Switzerland) (CH)
- Corresponding author
- Galimberti, Ivan
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-05
- Volume
- 39
- Issue
- 9
- Pages
- 110883
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4281772883
- Cited by
- 60
- References
- 22
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 12 · 2023: 26 · 2022: 5
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis Institutes for BioMedical Research
- 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, Alzheimer's disease, amyloid-beta pathology, microglial maturation, neuroinflammation, single-cell transcriptomics, mouse model
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Microglia, Mice
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