Unveiling microglial heterogeneity from single-cell transcriptomics in neurodegenerative diseases

Abstract

Microglia are key players in maintaining brain homeostasis and responding to pathological conditions. Their multifaceted roles in health and disease have garnered significant attention in the context of neurodegeneration. In recent years, single-cell transcriptomic techniques have provided unprecedented insights into microglial heterogeneity, revealing distinct subpopulations and gene expression patterns associated with neuroprotection or neurotoxicity. Here, the transcriptomic landscape of microglia has been dissected by leveraging human single-nuclei RNA sequencing datasets of neurodegenerative conditions, encompassing amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimers disease, aging, and Parkinsons disease. Results have led to the identification of distinct cell subpopulations, representative of the functional heterogeneity of the brain microglia. Moreover, distinct gene signatures and regulatory networks linked to inflammation and neurodegeneration have been identified. Overall, the study provides an improved portrait of microglia in the context of neurodegenerative disorders, and it holds promise for developing a more targeted research aimed at modulating microglial function to mitigate disease progression and foster neuroprotection. HighlightsO_LIBrain-resident microglia cells show a profound transcriptional heterogeneity C_LIO_LIMicroglia are not subject to a macrophage-like polarization mechanism C_LIO_LINeurodegenerative disorders share common transcriptional programs, yet retaining their own peculiarities C_LIO_LIDistinct gene regulatory networks underlie microglia heterogeneity and neurodegeneration-related dysfunctions C_LI