Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania.
Faculty of Pharmacy, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania.
Int J Mol Sci. 2023 Aug 1;24(15):12315. doi: 10.3390/ijms241512315.
Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ species-small oligomers, large oligomers, insoluble fibrils, and monomers-were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ oligomers induced a concentration- and time-dependent increase in intracellular Ca and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca nor viability was significantly affected by larger Aβ species or monomers. In addition, the small Aβ oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy.
阿尔茨海默病（AD）是全球最常见的痴呆症形式，占病例的 70%。AD 病理涉及异常淀粉样β（Aβ）积累，Aβ 结构与毒性之间的联系是主要关注点。NMDA 受体（NMDAR）被认为是受 Aβ影响的神经元中必不可少的，但该受体在神经胶质细胞损伤中的作用仍不清楚。此外，对于 Aβ 物种在神经元和神经胶质细胞中线粒体氧化还原状态中的作用知之甚少，这可能对开发 Aβ 引起的神经毒性至关重要。在这项研究中，我们研究了不同的 Aβ 物种-小寡聚体、大寡聚体、不溶性纤维和单体-是否能够通过小胶质细胞 NMDAR 激活和原代大鼠脑细胞培养物中线粒体氧化还原状态的变化产生神经毒性作用。小 Aβ 寡聚体诱导细胞内 Ca 浓度和时间依赖性增加和坏死性小胶质细胞死亡。这些变化部分被 NMDA 受体抑制剂 MK801、美金刚和 D-2-氨基-5-磷戊酸（DAP5）所阻止。较大的 Aβ 物种或单体均不会显著影响小胶质细胞内 Ca 或活力。此外，小 Aβ 寡聚体引起线粒体活性氧（mtROS）介导的线粒体去极化、谷氨酸释放和神经元细胞死亡。在小胶质细胞中，Aβ 诱导的 mtROS 过产生是由细胞内钙离子和 Aβ 结合的醇脱氢酶（ABAD）介导的。数据表明，针对小胶质细胞 NMDAR 和 mtROS 的药理学靶向可能是 AD 治疗的一种有前途的策略。
