Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies.
Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies.
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DOI：
10.1007/s12035-014-9053-6
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发表时间：
2016-01
影响因子：
5.1
通讯作者：
Tyagi, Neetu
中科院分区：
文献类型：
--
作者：
Kamat, Pradip K.;Kalani, Anuradha;Rai, Shivika;Swarnkar, Supriya;Tota, Santoshkumar;Nath, Chandishwar;Tyagi, Neetu
突触由神经元间的连接形成，允许神经元细胞将电或化学信号传递到另一个细胞。这一通道通常在大多数神经退行性疾病中受损或丢失。阿尔茨海默病（Alzheimer's disease，AD）患者的认知功能障碍与突触功能障碍和突触丢失有关。虽然AD的病理学标志是与氧化应激增加相关的老年斑、神经元缠结和神经元变性，但突触丢失是AD发病机制中的早期事件。主要激酶如丝裂原活化蛋白激酶（MAPK）、细胞外受体激酶（ERK）、钙调蛋白依赖性蛋白激酶（CaMKII）、糖原合成酶-3 β（GSK-3β）、cAMP反应元件结合蛋白（CREB）、钙调神经磷酸酶与氧化应激动态相关介导的异常过度磷酸化的tau蛋白，并表明这些激酶的改变可能专门参与AD的发病机制。N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）激活和β淀粉样蛋白（Aβ）毒性改变突触功能，这也与蛋白磷酸酶（PP）抑制和tau过度磷酸化（AD的两个主要事件）相关。然而，氧化应激参与突触功能障碍知之甚少。脑中氧化应激和自由基产生沿着兴奋性毒性导致神经元细胞死亡。从几项研究中推断，兴奋性毒性、自由基产生和由氧化应激引起的突触功能改变与AD病理学相关。NMDAR通过突触可塑性机制维持神经元兴奋性、Ca 2+内流和记忆形成。最近，我们报道了与NMDARs表达改变相关的突触氧化还原应激机制。我们认为，通过NMDAR介导的氧化应激及其与其他分子的相互作用可能是tau蛋白过度磷酸化和突触功能障碍的驱动力。因此，了解氧化应激机制和退化的突触是至关重要的治疗策略，旨在防止AD发病机制的发展。
Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer’s disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3β (GSK-3β), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Aβ) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca2+ influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.
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影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1152/ajpheart.00448.2003
发表时间：
2003-12-01
影响因子：
4.8
作者：
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通讯作者：
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作者：
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影响因子：
2.5
作者：
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