Adult human subventricular zone microglia promote a pro-neurogenic niche for neuronal progenitors in Parkinson's disease

Abstract

Neural stem cells (NSCs) in the subventricular zone (SVZ) of the mammalian brain become increasingly quiescent with aging, which correlates to increased inflammatory signals in the SVZ. Targeting cells that secrete inflammatory signals, such as microglia, could potentially re-activate NSCs. In this study, we characterized CD11b–positive microglia isolated from post-mortem SVZ from non-demented control (Aged), Alzheimer's disease (AD), and Parkinson's disease (PD) by single-cell and bulk RNA sequencing. Our transcriptome data revealed changes in gene signature in SVZ microglia from PD and AD, highlighting a disease-dependent response. Culture of iPSC-derived NSCs with supernatant from Aged, PD, and AD SVZ microglia showed an increase in proliferation and neuronal differentiation in the PD condition. Furthermore, we identified NR4A2, a transcription factor that promotes an anti-inflammatory microglia state, as a potential molecular mechanism that promotes a pro-neurogenic microglia phenotype. Altogether, our work identified a pro-neurogenic subpopulation of SVZ microglia that could be a novel target to promote repair in neurodegenerative diseases.