<i>Cspg4^high</i> microglia contribute to microgliosis during neurodegeneration.

Abstract

Microglia play a critical role in the pathogenic process of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). Upon pathological stimulation, microglia are converted from a surveillant to an overactivated phenotype. However, the molecular characters of proliferating microglia and their contributions to the pathogenesis of neurodegeneration remain unclear. Here, we identify chondroitin sulfate proteoglycan 4 (<i>Cspg4,</i> also known as neural/glial antigen 2)-expressing microglia as a specific subset of microglia with proliferative capability during neurodegeneration. We found that the percentage of <i>Cspg4⁺</i> microglia was increased in mouse models of PD. The transcriptomic analysis of <i>Cspg4⁺</i> microglia revealed that the subcluster <i>Cspg4^high</i> microglia displayed a unique transcriptomic signature, which was characterized by the enrichment of orthologous cell cycle genes and a lower expression of genes responsible for neuroinflammation and phagocytosis. Their gene signatures were also distinct from that of known disease-associated microglia. The proliferation of quiescent <i>Cspg4^high</i> microglia was evoked by pathological α-synuclein. Following the transplantation in the adult brain with the depletion of endogenous microglia, <i>Cspg4^high</i> microglia grafts showed higher survival rates than their <i>Cspg4</i>^- counterparts. Consistently, <i>Cspg4^high</i> microglia were detected in the brain of AD patients and displayed the expansion in animal models of AD. These findings suggest that <i>Cspg4^high</i> microglia are one of the origins of microgliosis during neurodegeneration and may open up a avenue for the treatment of neurodegenerative diseases.