Pathological substrate of memory impairment in multiple system atrophy
Pathological substrate of memory impairment in multiple system atrophy
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DOI：
10.1111/nan.12844
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发表时间：
2022-08-12
影响因子：
5
通讯作者：
Wakabayashi, Koichi
中科院分区：
文献类型：
--
作者：
Miki, Yasuo;Tanji, Kunikazu;Wakabayashi, Koichi
目的：帕金森病的突触功能障碍是由致病性α-突触核蛋白在神经元之间的传播引起的。以前，在多系统萎缩（MSA），病理特征异常α-突触核蛋白主要在少突胶质细胞异位沉积，我们证明了记忆障碍的发生与海马中α-突触核蛋白阳性神经元胞质包涵体（NCIs）的数量有关。在本研究中，我们的目的是探讨如何异常的α-突触核蛋白在海马会导致记忆defiction.Methods：我们进行了病理和生化分析，使用小鼠模型的成年发病的MSA和人类病例（MSA，N = 25;帕金森氏病，N = 3;阿尔茨海默氏病，N = 2;正常对照，N = 11）。此外，MSA模型小鼠的行为和physiologically.Results：在MSA模型中，诱导型人α-synuclein首先在少突胶质细胞中表达，随后在兴奋性海马神经元（NCI-like结构）及其突触前神经末梢的细胞质中积累，并伴随记忆障碍的发展。α-突触核蛋白寡聚体在MSA模型的海马体中同时增加。海马树突棘的数量也减少，其次是抑制长时程增强。与这些研究结果中获得的MSA模型一致，尸检分析的人MSA脑组织表明，MSA与记忆障碍的情况下，开发更多的NCIs兴奋性海马神经元沿着与α-突触核蛋白寡聚体比那些没有。结论：我们的研究结果提供了新的见解α-突触核蛋白寡聚体的作用，作为一个可能的病理原因，记忆障碍的MSA。
Aims: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic alpha-synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal alpha-synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of alpha-synuclein-positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal alpha-synuclein in the hippocampus can lead to memory impairment.Methods: We performed pathological and biochemical analyses using a mouse model of adult-onset MSA and human cases (MSA, N = 25; Parkinson's disease, N = 3; Alzheimer's disease, N = 2; normal controls, N = 11). In addition, the MSA model mice were examined behaviourally and physiologically.Results: In the MSA model, inducible human alpha-synuclein was first expressed in oligodendrocytes and subsequently accumulated in the cytoplasm of excitatory hippocampal neurons (NCI-like structures) and their presynaptic nerve terminals with the development of memory impairment. alpha-Synuclein oligomers increased simultaneously in the hippocampus of the MSA model. Hippocampal dendritic spines also decreased in number, followed by suppression of long-term potentiation. Consistent with these findings obtained in the MSA model, post-mortem analysis of human MSA brain tissues showed that cases of MSA with memory impairment developed more NCIs in excitatory hippocampal neurons along with alpha-synuclein oligomers than those without.Conclusions: Our results provide new insights into the role of alpha-synuclein oligomers as a possible pathological cause of memory impairment in MSA.