Astrocyte-specific inhibition of primary cilium functions improves cognitive impairment during neuroinflammation by suppressing A1 astrocyte differentiation
bioRxiv (Cold Spring Harbor Laboratory)(2023)
摘要
A1 astrocytes play a neurotoxic role in various neurodegenerative diseases. While inhibiting the differentiation of A1 astrocytes can slow disease progression, the mechanisms controlling A1 astrocyte differentiation are largely unknown. The primary cilium is a cellular organelle that receives extracellular signals and regulates cell proliferation, differentiation, and maturation. To elucidate the physiological function of the primary cilium in A1 astrocytes, we utilized primary astrocytes and an inflammation mouse model. We found that the length of the primary cilium was increased in astrocytes, and the inhibition of primary cilium formation inhibited their differentiation into A1 astrocytes. Since mice with systemic ciliogenesis defects exhibit embryonic lethality, the function of the primary cilium in adults has remained largely unclear. Therefore, we established conditional knockout (cKO) mice that specifically inhibit primary cilium function in astrocytes upon drug stimulation. In a neuroinflammation mouse model in which lipopolysaccharide (LPS) was intraperitoneally injected into wild-type mice, increases in A1 astrocyte number and primary cilium length were observed in the brain. In contrast, cKO mice exhibited a reduction in the proportions of A1 astrocytes and apoptotic cells in the brain. Additionally, the novel object recognition (NOR) score observed in the cKO mice was higher than that observed in the neuroinflammation model mice. These results suggest that the primary cilium in astrocytes is essential for A1 astrocyte differentiation, which leads to a decline brain function. We propose that regulating astrocyte-specific primary cilium signalling may be a novel strategy for the suppression of neuroinflammation.
### Competing Interest Statement
The authors have declared no competing interest.
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关键词
primary cilium functions,a1 astrocyte-specific differentiation,cognitive impairment,neuroinflammation
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