Kamat Pradip K, Kalani Anuradha, Rai Shivika, Swarnkar Supriya, Tota Santoshkumar, Nath Chandishwar, Tyagi Neetu
Division of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.
Division of Pharmacology, Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, 226001, UP, India.
Mol Neurobiol. 2016 Jan;53(1):648-661. doi: 10.1007/s12035-014-9053-6. Epub 2014 Dec 17.
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, Ca(2+) 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.
突触由神经元间连接形成，使一个神经元细胞能够将电信号或化学信号传递给另一个细胞。在大多数神经退行性疾病中，这种信号传递通常会受损或丧失。人们普遍认为，突触功能障碍和突触丧失是导致阿尔茨海默病（AD）患者认知缺陷的原因。尽管AD的病理特征是老年斑、神经原纤维缠结和与氧化应激增加相关的神经元变性，但突触丧失是AD发病机制中的早期事件。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）、糖原合酶-3β（GSK-3β）、cAMP反应元件结合蛋白（CREB）和钙调神经磷酸酶等主要激酶的参与与氧化应激介导的tau异常过度磷酸化动态相关，这表明这些激酶的改变可能专门参与了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）毒性会改变突触功能，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，氧化应激在突触功能障碍中的作用尚不清楚。大脑中的氧化应激和自由基生成以及兴奋性毒性会导致神经元细胞死亡。多项研究推断，氧化应激所引发的兴奋性毒性、自由基生成和突触功能改变与AD病理相关。NMDARs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对于开发旨在预防AD发病机制的治疗策略至关重要。
