A research team led by Dr. ZHOU Jiawei at the Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology of the Chinese Academy of Sciences found that Cspg4^high microglia is a new cell source for microgliosis in neurodegeneration. They unraveled the molecular characteristics and functions of Cspg4^high microglia which showed high capability of cell proliferation in neurodegenerative diseases thus providing a new insight into the pathogenesis of  neurodegenerative diseases. . 

Emerging evidence has strongly suggested that microglia are a key player in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Upon pathological stimulation, microglia, resident immune cells in the brain, are rapidly activated and migrate toward the injured brain sites. Activated microglia play crucial roles in neuroinflammation, protein deposition and phagocytosis. Aberrant activation of these cells is considered to contribute significantly to the initiation and progression of neurodegenerative diseases. It has been suggested that microglia may be used for early diagnosis and treatment of neurodegenerative diseases. However, the origin of activated microglia during neurodegeneration remains incompletely understood. Traditionally, activated microglial cells in the brain have been believed to originate from themselves and the bone marrow-derived precursor cells. Understanding their origin is essential for controlling deregulated microglial activity.  

The authors identified chondroitin sulfate proteoglycan 4 (Cspg4, also known as neural/glial antigen 2)-expressing microglia as a specific subset of microglia with proliferative capability during neurodegeneration. The percentage of Cspg4⁺ microglia was increased in mouse models of PD. Transcriptome analysis of Cspg4⁺ microglia revealed that the subcluster Cspg4^high microglia displayed a unique transcriptomic signature, which was characterized by 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 Cspg4^high microglia was evoked by pathological a-synuclein. Following transplantation in the adult brain with depletion of endogenous microglia, Cspg4^high microglia grafts showed higher survival rates than their Cspg4^—counterparts. Consistently, Cspg4^high microglia were detected in the brain of AD patients and displayed the expansion in animal models of AD. These findings suggest that Cspg4^high microglia are one of the origins of microgliosis during neurodegeneration and may open up a new avenue for the treatment of neurodegenerative diseases.   

This work entitled “Cspg4high microglia contribute to microgliosis during neurodegeneration” was published online in PNAS on February 17, 2023. This work was mostly completed by graduate student LIU Yajing under the supervision of Professors ZHOU Jiawei and HU Gang (Nanjing University of Chinese Medicine). Ms. DING Yu (Nanjing University of Chinese Medicine), YIN Yanqing and XIAO Hui made important contributions. The optical imaging platform and the animal platform in the institution provided technical support. This work was sponsored by the Ministry of Science and Technology, National Natural Science Foundation, Chinese Academy of Sciences, Shanghai Municipal Science and Technology Commission, and Department of Science and Technology of Guangdong Province. 

Figure. The percentage of Cspg4⁺ microglia is increased in an animal model of Parkinson’s disease.  (Image by CEBSIT)

AUTHOR CONTACT:  

ZHOU Jiawei 

Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China 

E-mail: jwzhou@ion.ac.cn