Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary.
MTA-SZTE Neuroscience Research Group, Szeged, Hungary.
J Alzheimers Dis. 2018;62(2):523-547. doi: 10.3233/JAD-170929.
The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.
阿尔茨海默病（AD）的发病机制肯定涉及线粒体紊乱、谷氨酸兴奋性毒性和神经炎症。AD 中线粒体功能障碍的三个主要方面，即动力学缺陷、改变的生物能量学和缺陷的转运，协同作用。此外，谷氨酸能神经传递受到多种方式的影响。突触和 extrasynaptic 谷氨酸能传递之间的平衡向 extrasynaptic 位点转移，导致谷氨酸兴奋性毒性，这种现象因谷氨酸释放增加和谷氨酸摄取减少而加剧。AD 中的神经炎症主要与先天免疫系统的中枢参与者有关，中枢神经系统 (CNS) 驻留的小胶质细胞、星形胶质细胞和血管周围巨噬细胞在细胞水平上被牵连。已经描述了与 AD 中色氨酸代谢的犬尿氨酸 (KYN) 途径的某些步骤的激活有关的几种异常。首先，该途径的第一步和限速步骤，色氨酸 2,3-双加氧酶的激活得到了很好的证明。3-羟基-L-KYN 和其代谢物 3-羟基邻氨基苯甲酸具有促氧化剂、抗氧化剂和有效的免疫调节特性，这使得它们在 AD 中的改变具有相关性。另一种代谢物喹啉酸已被证明具有神经毒性，可促进谷氨酸兴奋性毒性、活性氧物质的产生、脂质过氧化和小胶质细胞神经炎症，并且其在 AD 病理中的大量存在已得到证明。最后，神经保护代谢物，犬尿氨酸酸，与谷氨酸受体的拮抗作用、自由基清除和免疫调节有关，这为潜在的治疗方法提供了依据。这篇综述介绍了 KYN 途径相关改变与 AD 发病机制的三个主要领域，如线粒体功能障碍、兴奋性毒性和神经炎症之间的多种联系，暗示了可能的治疗选择。
