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A microglia clonal inflammatory disorder in Alzheimer's disease
Rocio Vicario1, Stamatina Fragkogianni1, Leslie Weber1
1Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, United States.
Abstract:
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer's disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.
Insights
Somatic mutations in microglia may drive Alzheimer's disease (AD). Researchers found specific mutated microglia clones in AD patients, activating inflammatory pathways linked to neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Somatic genetic heterogeneity is common in human tissues and linked to disease.
- Its role in neurodegenerative diseases like Alzheimer's disease (AD) is understudied.
- Microglia, the brain's immune cells, are increasingly implicated in AD pathogenesis.
Purpose of the Study:
- To investigate the role of somatic mutations in microglia in Alzheimer's disease.
- To identify specific genetic variants enriched in microglia from AD patients.
- To explore the functional consequences of these variants on microglial activity and neuroinflammation.
Main Methods:
- Comparative analysis of microglial genetic profiles from AD patients and controls.
- Identification of pathogenic variants using next-generation sequencing.
- In vitro and in vivo studies to assess the functional impact of identified variants on MAPK pathway activation and microglial inflammatory responses.
Main Results:
- Selective enrichment of microglia clones with pathogenic variants in AD patients compared to controls.
- These variants were specific to microglia and not found in other cell types or blood.
- AD-associated variants frequently targeted the MAPK pathway, including CBL mutations, leading to ERK activation and a pro-inflammatory microglial phenotype.
Conclusions:
- Somatic mutations in microglia, particularly those affecting the MAPK pathway, are selectively enriched in Alzheimer's disease.
- These mutations activate microglia, promoting a neuroinflammatory response that may contribute to AD-related neurodegeneration.
- Targeting these mutated microglia or the MAPK pathway could offer novel therapeutic strategies for AD.
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