A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam.
A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam.
复制标题
SV2a 蛋白在衰老和阿尔茨海默病中的线粒体作用：左乙拉西坦的研究。
DOI：
--
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
W. Müller
中科院分区：
文献类型：
--
作者：
Carola Stockburger;D. Miano;Marion Baeumlisberger;Thea Pallas;Tabiwang N. Arrey;M. Karas;Kristina Friedland;W. Müller
异常的神经元网络活动与神经元的过度兴奋有关，这似乎是衰老和阿尔茨海默病（AD）中认知能力下降的重要原因。在许多抗癫痫药物中，只有左乙拉西坦通过减少过度兴奋来改善AD患者和AD动物模型的认知功能障碍。由于抑制性中间神经元功能受损，而不是过度活跃的神经元，似乎是根本原因，改善受损的神经元功能，而不是平静过度活跃的神经元可能是相关的解释缺乏活性的其他抗癫痫药。有趣的是，左乙拉西坦改善由低水平可溶性Aβ引起的认知缺陷，同时改善突触功能和可塑性。由于Aβ对突触可塑性的负面影响与线粒体功能障碍密切相关，我们推测左乙拉西坦对突触活性的影响可能是通过改善线粒体功能而提高的。因此，我们研究了左乙拉西坦对与衰老和AD相关的线粒体功能障碍相关的神经元缺陷的可能影响。左乙拉西坦改善了线粒体功能障碍的几个方面，包括衰老和早期晚发性AD细胞模型中裂变和融合平衡的改变。我们首次证明，使用免疫组织化学和蛋白质组学，突触囊泡蛋白2A（SV2a），左乙拉西坦的分子靶点，在线粒体中表达。此外，左乙拉西坦对线粒体通透性转换孔的开放具有显著影响。重要的是，当使用siRNA敲低SV2a时，左乙拉西坦的作用显著消除。总之，在线粒体水平上干扰SV2a蛋白，从而改善线粒体功能可能代表左乙拉西坦改善迟发性AD症状的额外治疗作用。
Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.
登录
查看更多内容
DOI：
10.3233/jad-2010-100504
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Reddy PH;Manczak M;Mao P;Calkins MJ;Reddy AP;Shirendeb U
通讯作者：
Shirendeb U
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
DOI：
10.1016/j.bbadis.2011.08.012
发表时间：
2011-12
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Swerdlow RH
通讯作者：
Swerdlow RH
DOI：
10.1016/j.bbadis.2013.09.010
发表时间：
2014-08
影响因子：
6.2
作者：
Swerdlow, Russell H.;Burns, Jeffrey M.;Khan, Shaharyar M.
通讯作者：
Khan, Shaharyar M.
影响因子：
56.9
作者：
Busche, Marc Aurel;Eichhoff, Gerhard;Garaschuk, Olga
通讯作者：
Garaschuk, Olga