在阿尔茨海默病模型中，C5aR1信号传导促进区域和年龄依赖性的突触修剪。
C5aR1 signaling promotes region and age dependent synaptic pruning in models of Alzheimer's Disease.
作者信息
Gomez-Arboledas Angela, Fonseca Maria I, Kramar Enikö, Chu Shu-Hui, Schartz Nicole, Selvan Purnika, Wood Marcelo A, Tenner Andrea J
机构信息
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA.
出版信息
bioRxiv. 2023 Oct 2:2023.09.29.560234. doi: 10.1101/2023.09.29.560234.
INTRODUCTION
Synaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD.
METHODS
A combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD.
RESULTS
Genetic ablation or pharmacological inhibition of C5aR1 rescues the excessive pre-synaptic pruning and synaptic loss in an age and region dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP).
DISCUSSION
Reduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.
引言
突触丧失是阿尔茨海默病（AD）的一个标志，与AD患者的认知衰退相关。补体介导的突触修剪与AD中这种过度的突触丧失有关。在此，我们研究了C5aR1抑制对两种AD小鼠模型中微胶质细胞和星形胶质细胞突触修剪的影响。
方法
使用超分辨率、共聚焦和三维图像重建相结合的方法，评估C5aR1基因敲除或药物抑制对AD的北极48和Tg2576模型的影响。
结果
在两种AD小鼠模型中，C5aR1基因敲除或药物抑制以年龄和区域依赖的方式挽救了过度的突触前修剪和突触丧失，这与改善的长时程增强（LTP）相关。
讨论
减少过度的突触修剪是抑制C5a-C5aR1信号传导的另一个有益结果，进一步支持其作为治疗AD的有效靶向疗法的潜力。
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