Adult human subventricular zone microglia promote a protective niche for neuronal progenitors in Parkinson’s Disease

Neural stem cells (NSCs) of the subventricular zone (SVZ) of the mammalian brain become increasingly quiescent with aging, which correlates to increased inflammatory signals in the SVZ. Therefore, targeting cells that secrete inflammatory signals, such as microglia cells, could potentially re-activate NSCs. In this study we characterized CD11b‑positive microglia isolated from fresh post-mortem SVZ tissue from non-demented control (Aged), Alzheimer’s disease (AD), and Parkinson’s disease (PD) donors by single-cell RNA sequencing and bulk RNA sequencing. Our transcriptome data revealed changes in gene signature of microglia from the SVZ of PD and AD patients, highlighting a dynamic and disease-dependent response. To determine how these differences in gene signature translated into microglia function, iPSC-derived NSCs were cultured with supernatant from SVZ microglia isolated from Aged, PD, and AD donors. Our data showed a significant increase in proliferation and neuronal differentiation in the PD condition. Furthermore, we identified NR4A2, which encodes for a transcription factor that promotes an anti-inflammatory phenotype in microglia, as a potential molecular mechanism that promotes a more neuroprotective phenotype in microglia. Altogether, our work identified a neuroprotective subpopulation of SVZ microglia that could be a novel target to promote repair in neurodegenerative diseases.