Astrocyte-derived CHI3L1 signaling impairs neurogenesis and cognition in the demyelinated hippocampus
Yanna Song,
Wei Jiang,
Shabbir Khan Afridi,
Tongtong Wang,
Fan Zhu,
Huiming Xu,
Faisal Hayat Nazir,
Chunxin Liu,
Yuge Wang,
Youming Long,
Yu-Wen Alvin Huang,
Wei Qiu,
Changyong Tang
Affiliations
Yanna Song
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
Wei Jiang
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
Shabbir Khan Afridi
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
Tongtong Wang
Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
Fan Zhu
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
Huiming Xu
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
Faisal Hayat Nazir
Nash Family Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Chunxin Liu
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
Yuge Wang
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
Youming Long
Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou 510260, Guangdong Province, China; Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, 250 Changgang East Road, Guangzhou 510260, Guangdong Province, China
Yu-Wen Alvin Huang
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02903, USA
Wei Qiu
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China; Corresponding author
Changyong Tang
Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University; 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China; Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Corresponding author
Summary: Cognitive dysfunction is a feature in multiple sclerosis (MS), a chronic inflammatory demyelinating disorder. A notable aspect of MS brains is hippocampal demyelination, which is closely associated with cognitive decline. However, the mechanisms underlying this phenomenon remain unclear. Chitinase-3-like (CHI3L1), secreted by activated astrocytes, has been identified as a biomarker for MS progression. Our study investigates CHI3L1’s function within the demyelinating hippocampus and demonstrates a correlation between CHI3L1 expression and cognitive impairment in patients with MS. Activated astrocytes release CHI3L1 in reaction to induced demyelination, which adversely affects the proliferation and differentiation of neural stem cells and impairs dendritic growth, complexity, and spine formation in neurons. Our findings indicate that the astrocytic deletion of CHI3L1 can mitigate neurogenic deficits and cognitive dysfunction. We showed that CHI3L1 interacts with CRTH2/receptor for advanced glycation end (RAGE) by attenuating β-catenin signaling. The reactivation of β-catenin signaling can revitalize neurogenesis, which holds promise for therapy of inflammatory demyelination.
