Astrocyte-secreted C3 signaling impairs neuronal development and cognition in autoimmune diseases

作者：Fan Zhu, Pengyan He, Wei Jiang, Shabbir Khan Afridi, Huiming Xu, Maali Alahmad, Yu‐Wen Alvin Huang, Wei Qiu, Guangyou Wang, Changyong Tang · 发表于：Progress in Neurobiology · 年份：2024 · DOI：10.1016/j.pneurobio.2024.102654 · 被引用次数：15 · 研究领域：Adenosine and Purinergic Signaling、Neuroinflammation and Neurodegeneration Mechanisms、Phagocytosis and Immune Regulation

Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening β-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3β/β-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectivel...