| Popis: |
Background: Research in recent years firmly established that microglial cells play an important role in the pathogenesis of Alzheimer's disease (AD). In parallel, a series of studies showed that, under both homeostatic and pathological conditions, microglia are a heterogeneous cell population. In AD, amyloid-b (Ab) plaque-associated microglia (PAM) display a clearly distinct phenotype compared to plaque-distant microglia (PCM), suggesting that these two microglia subtypes likely differently contribute to disease progression. So far, molecular characterization of PAM was performed indirectly using scRNA-seq approaches or based on markers that are supposedly up-regulated in this microglia subpopulation.Methods: In this study, we combined cell-specific laser capture and RNA-seq analysis to investigate, without preconceived notions of the molecular and/or functional changes that would affect these cells, the functional role of both plaque-associated and plaque-distant microglia. Results: First, we established that this approach allows selective isolation of microglia, while preserving spatial information and preventing transcriptome changes induced by classical purification approaches. Then, we identified, in PAM and PCM subpopulations, networks of co-deregulated genes and analyzed their potential functional roles in AD. Finally, we investigated the dynamics of microglia transcriptomic remodeling at early, intermediate and late stages of the disease. Conclusions: Our comprehensive study demonstrates that the proximity of microglia to Ab-plaques dramatically alters the microglial transcriptome and reveals that these changes can have both positive and negative impacts on the surrounding cells. These opposing effects may be driven by local microglia heterogeneity also demonstrated by this study. Our results also suggest that Ab plaque-associated microglia undergo exhaustion in the later stage of the disease. Our approach leads to molecularly define the overlooked plaque-distant microglia. We show that plaque-distant microglia are not bystanders of the disease, although the transcriptomic changes are far less striking compared to what is observed in plaque-associated microglia. In particular, our results suggest they are involved in Ab oligomer detection and in Ab-plaque initiation, with increased contribution as the disease progresses. |
