Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer's disease.
Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer's disease.
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DOI：
10.1186/s13024-023-00636-1
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发表时间：
2023-07-03
影响因子：
15.1
通讯作者：
Wei, Ling
中科院分区：
文献类型：
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作者：
Yu, Shan P.;Jiang, Michael Q.;Shim, Seong S.;Pourkhodadad, Soheila;Wei, Ling
关键词：
中风和迟发性阿尔茨海默病（AD）是彼此的危险因素;这些大脑疾病在老年人中的合并症是基础研究和临床实践中的一个重大挑战。然而，卒中和AD在发病机制和病理生理学方面的相似性和差异很少被回顾。本文就脑卒中与迟发性AD及相关痴呆（ADRD）共病的研究背景和最新进展作一综述。谷氨酸能NMDA受体（NMDAR）活性和NMDAR介导的Ca 2+内流对于神经元功能和细胞存活是必不可少的。然而，缺血性损伤可引起谷氨酸浓度的快速增加和NMDAR的过度激活，导致神经元细胞中的迅速Ca 2+过载和数小时和数天内的急性兴奋性毒性。另一方面，在AD动物模型和患者中常见的NMDAR活性的轻度上调不会立即产生细胞毒性。然而，持续数月至数年的持续NMDAR过度活跃和Ca 2+失调可能是AD/ADRD发展中缓慢演变事件（即退行性兴奋性毒性）的致病因素。具体而言，由突触外NMDAR（eNMDAR）介导的Ca 2+内流和由瞬时受体电位阳离子通道亚家族M成员（TRPM）介导的下游途径是兴奋性毒性的主要原因。另一方面，NMDAR亚基GluN 3A在NMDAR活性中起“看门人”作用，并对急性和慢性兴奋性毒性起神经保护作用。因此，缺血性卒中和AD共享NMDAR和Ca 2+介导的致病机制，为预防性和可能的疾病修饰疗法提供了共同的受体靶点。美金刚胺（MEM）优先阻断eNMDAR，并且被联邦药物管理局（FDA）批准用于具有可变功效的中重度AD的对症治疗。根据eNMDAR的致病作用，可以想象MEM和其他eNMDAR拮抗剂应更早给药，优选在AD/ADRD的症状前阶段给药。这种抗AD治疗可以同时作为针对≥ 50% AD患者发作的中风的预处理策略。未来对NMDARs的调控、eNMDARs的持久控制、Ca 2+稳态和下游事件的研究将为理解和治疗AD/ADRD和卒中的共病提供有希望的机会。在线版本包含补充材料，可通过10.1186/s13024-023-00636-1获得。
Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca2+ influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca2+ overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca2+ dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca2+ influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a “gatekeeper” role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca2+-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca2+ homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke. The online version contains supplementary material available at 10.1186/s13024-023-00636-1.
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