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New Cell Source Found To Contribute to Microgliosis During Neurodegeneration

Representation of human cells.
Credit: Arek Socha, Pixabay
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In a study published in PNAS, 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 Cspg4high microglia is a new cell source for microgliosis in neurodegeneration, and unraveled the molecular characteristics and functions of Cspg4high 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.

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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 researchers 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 Parkinson’s disease. Transcriptome analysis of Cspg4+ microglia revealed that the subcluster Cspg4high 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 Cspg4high microglia was evoked by pathological a-synuclein. Following transplantation in the adult brain with depletion of endogenous microglia, Cspg4high microglia grafts showed higher survival rates than their Cspg4-counterparts.

Consistently, Cspg4high microglia were detected in the brain of Alzheimer’s disease patients and displayed the expansion in animal models of Alzheimer’s disease.

These findings suggest that Cspg4high microglia are one of the origins of microgliosis during neurodegeneration and may open up a new avenue for the treatment of neurodegenerative diseases.

Reference: Liu Y jing, Ding Y, Yin Y qing, Xiao H, Hu G, Zhou J wei. Cspg4 high microglia contribute to microgliosis during neurodegeneration. Proc Natl Acad Sci USA. 2023;120(8):e2210643120. doi: 10.1073/pnas.2210643120

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