August Yue Huang, et al. – Broad Institute of MIT and Harvard.
Background: Somatic DNA mutations, leading to clonal expansion of mutant cells, accumulate in cells during aging and are linked to cancer and other diseases. It is unclear whether somatic mutations are more prevalent in AD, particularly in microglia.
This Study: Using 3 distinct approaches on samples from 3 cohorts, Huang and colleagues analyzed the prevalence of somatic mutations in AD.
- Brain samples from cerebral cortex revealed a higher prevalence of somatic mutations in patients. This was not observed in samples from cerebellum, a region largely unaffected in AD, indicating specificity for regions affected by AD.
- Selecting for nuclei from microglia revealed that somatic mutations are particularly prevalent in this cell type compared to neurons from the same sample.
- Microglia had up to 438-fold higher levels of mutations to tumor-suppressor genes compared to neurons, suggesting increased proliferation of these mutant microglia.
- Mutant microglia had pro-inflammatory patterns of gene expression.
Bottom Line: Higher levels of somatic mutations, particularly to tumor-suppressor genes, are a hallmark of microglia in AD.
Open Questions:
- Are these somatic mutations present early in the microglia cell lineage, representing a predisposing risk factor?
- Are microglia that randomly develop these mutations selected for during AD?
