β-淀粉样蛋白（1-42）与α-突触核蛋白对海马神经元突触功能障碍的协同作用。

The synergistic effect between β-amyloid(1-42) and α-synuclein on the synapses dysfunction in hippocampal neurons.

作者信息

Wang Yixuan, Yu Zheming, Ren Huimin, Wang Jian, Wu Jianjun, Chen Yan, Ding Zhengtong

机构信息

Department of Neurology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department & Institute of Neurology, Shanghai Medical College, Fudan University, Shanghai 200040, China.

出版信息

J Chem Neuroanat. 2015 Jan;63:1-5. doi: 10.1016/j.jchemneu.2014.11.001. Epub 2014 Nov 15.

DOI:10.1016/j.jchemneu.2014.11.001

PMID:25445382

Abstract

OBJECTIVE

This study was to explore the molecular mechanisms underpinning the synergetic effect between β-amyloid (Aβ) and α-synuclein (α-syn) on synapses dysfunction during the development of neurodegenerative disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Alzheimer disease (AD).

METHODS

The primary cultured hippocampal neurons prepared from the fetal tissue of mice were divided into six groups and treated with DMSO, Aβ(42-1), α-syn, Aβ(1-42), α-syn plus Aβ(42-1) and α-syn plus Aβ(1-42), respectively. After incubation for 24 h, the synapsin I content was calculated by immunofluorescence and the synaptic vesicle recycling was monitored by FM1-43 staining. Furthermore, the expression of cysteine string protein-α (CSPα) detected by western blot was also conducted.

RESULTS

Either Aβ(1-42) or α-syn alone could induce a significant synapses dysfunction through reducing the content of synapsin I, inhibiting the synaptic vesicle recycling as well as down-regulating the expression of CSPα compared with the controls (P<0.05). However, simultaneous intervention with both α-syn and Aβ(1-42) aggravated these effects in cultured hippocampal neurons compared with the treatment with α-syn (synapsin I content: P<0.001; synaptic vesicle recycling: P=0.007; CSPα expression: P<0.001) or Aβ(1-42) (synapsin I number: P<0.001; synaptic vesicle recycling: P=0.007 CSPα expression: P<0.001) alone.

CONCLUSION

There was synergistic effect between Aβ and α-syn on synapses dysfunction through reducing the synapsin I content, inhibiting the synaptic vesicle recycling and down-regulating the expression of CSPα in several neurodegenerative diseases.

摘要

目的

本研究旨在探讨β-淀粉样蛋白（Aβ）和α-突触核蛋白（α-syn）在包括帕金森病（PD）、路易体痴呆（DLB）和阿尔茨海默病（AD）在内的神经退行性疾病发展过程中对突触功能障碍产生协同作用的分子机制。

方法

将从小鼠胚胎组织制备的原代培养海马神经元分为六组，分别用二甲基亚砜（DMSO）、Aβ（42-1）、α-syn、Aβ（1-42）、α-syn加Aβ（42-1）和α-syn加Aβ（1-42）处理。孵育24小时后，通过免疫荧光计算突触素I含量，并用FM1-43染色监测突触小泡循环。此外，还通过蛋白质免疫印迹法检测了半胱氨酸串珠蛋白-α（CSPα）的表达。

结果

与对照组相比，单独的Aβ（1-42）或α-syn均可通过降低突触素I含量、抑制突触小泡循环以及下调CSPα表达，诱导显著的突触功能障碍（P<0.05）。然而，与单独用α-syn（突触素I含量：P<0.001；突触小泡循环：P=0.007；CSPα表达：P<0.001）或Aβ（1-42）（突触素I数量：P<0.001；突触小泡循环：P=0.007；CSPα表达：P<0.001）处理相比，同时用α-syn和Aβ（1-42）干预可加重培养海马神经元中的这些效应。