TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease
Open accessAbstract
Dementia in general, and Alzheimer’s disease (AD) in particular, are age-related diseases 1,2 . AD is associated with multiple causative factors 3,4 , among which local brain inflammation plays a significant role 5 . Microglia, the brain-resident immune cells 6,7 , are activated along the disease course 7 . Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor 8,9 . A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-737 10,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.
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The senescence signature is TREM2 genotype dependent.
“Additional supportive evidence of β-amyloid induced senescence have come from demonstration of the TREM2 genotype dependence of the senescence signature (see also recent preclinical evidence presented in pre-print [56]).”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [56]
Preclinical studies using different models have suggested that senolytic treatments can reduce the abundance of senescent cells, disease-relevant pathology and cognitive deficits.
“Preclinical studies using different models have suggested that senolytic treatments can reduce the abundance of senescent cells, disease-relevant pathology and cognitive deficits [8, 56, 80].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [56]
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- Authors
- Rachmian, N., Medina, S., Cherqui, U., Akiva, H., Deitch, D., Edilbi, D., Croese, T., Salame, T., Peralta Ramos, J., Cahalon, L., Krizhanovsky, V., & Schwartz, M.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Krizhanovsky, V.
- Schwartz, M.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-03-21
- OpenAlex
- W4360609725
- Cited by
- 6
- References
- 51
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- H2020 European Research Council (856487)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- TREM2, microglial senescence, Alzheimer's disease, brain aging, microglial activation, senolysis, ABT-737, amyloidosis, tauopathy, cognitive decline, neuroinflammation
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