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

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2024-06-28 DOI:10.1016/j.pneurobio.2024.102654
Fan Zhu , Pengyan He , Wei Jiang , Shabbir Khan Afridi , Huiming Xu , Maali Alahmad , Yu-Wen Alvin Huang , Wei Qiu , Guangyou Wang , Changyong Tang
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Abstract

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. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases.

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星形胶质细胞分泌的C3信号损害自身免疫性疾病的神经元发育和认知能力
神经脊髓炎(NMO)是由针对星形胶质蛋白水通道蛋白 4(AQP4)的自身抗体诱发的原发性星形胶质细胞病变引起的,会导致严重的神经系统后遗症,如视力丧失、运动障碍和认知能力下降。越来越多的证据表明,补体成分激活失调是导致 NMO 发病的原因之一。研究表明,缺乏补体 C3 可防止神经退行性疾病(如阿尔茨海默病)和自身免疫性疾病(如多发性硬化症)中的海马神经变性和认知能力下降。然而,抑制 C3 信号传导能否改善 NMO 的认知功能障碍仍不清楚。在这项研究中,我们发现 C3a(C3 的分裂产物)的水平与患者队列中的认知障碍有显著相关性。在AQP4自身抗体的刺激下,星形胶质细胞被激活分泌补体C3,从而抑制了培养神经元树突轴化的发展。NMO小鼠模型表现出成年海马新生神经元树突和脊柱发育减少,以及学习和记忆功能受损,而降低星形胶质细胞中的C3水平可以挽救这些症状。从机理上讲,我们发现C3a与C3aR相互作用,通过抑制β-catenin信号来损害神经元的发育。此外,抑制 C3-C3aR-GSK3β/β-catenin 级联可恢复神经元发育并改善认知障碍。总之,我们的研究结果表明,C3-C3aR网络的激活通过介导星形胶质细胞和成神经元之间的交流,在神经元发育和认知过程中发挥着关键作用,是自身免疫相关认知障碍疾病的潜在治疗靶点。
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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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