Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer's Neuropathology.
Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer's Neuropathology.
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DOI：
10.1523/jneurosci.0295-20.2020
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发表时间：
2021-01-20
期刊：
影响因子：
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通讯作者：
Taglialatela G
中科院分区：
文献类型：
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作者：
Fracassi A;Marcatti M;Zolochevska O;Tabor N;Woltjer R;Moreno S;Taglialatela G
阿尔茨海默病 (AD) 的特点是大脑皮层进行性神经变性，其组织病理学特征是β淀粉样蛋白 (Aβ) 细胞外斑块和细胞内神经原纤维缠结（由过度磷酸化的 tau 蛋白构成）。这些病理特征与痴呆之间的相关性受到“阿尔茨海默病神经病理学非痴呆”（NDAN）个体的出现的挑战，尽管这些个体表现出 AD 的病理特征，但认知能力完好。这些受试者的存在表明，一些未知的机制被触发来抵抗 Aβ 介导的有害事件。 Aβ 积累影响线粒体氧化还原平衡，增加氧化应激状态，这反过来被认为是 AD 发病机制的主要原因。为了阐明 Aβ、氧化应激和认知障碍之间的关系，我们对 AD、NDAN 和年龄匹配的人类死后额叶皮质（无论性别）进行了比较研究。我们定量分析了氧化损伤标志物的免疫荧光分布，以及作为抗氧化反应关键因素的 SOD2（超氧化物歧化酶 2）、PGC1α [过氧化物酶体增殖物激活受体 (PPAR) γ 共激活剂 1α]、PPARα 和过氧化氢酶，以及作为 PGC1α 上游的 miRNA-485 的表达。 调节器。我们的结果证实了严重的氧化还原失衡，与 AD 大脑中的抗氧化防御受损有关。相比之下，NDAN 个体表现出较低的氧化损伤，这与高水平的清除系统有关，可能是由于缺乏 PGC1α miRNA-485 相关抑制所致。神经元和星形胶质细胞的比较分析进一步强调了抵消氧化还原失衡的细胞特异性机制。总的来说，我们的数据强调了 AD 中抗氧化反应的转录和转录后调节的重要性。这表明有效的 PGC1α 依赖性“安全机制”可以预防 Aβ 介导的氧化应激，支持旨在改善 AD 患者抗氧化反应途径缺陷的神经保护疗法。
Alzheimer's disease (AD) is characterized by progressive neurodegeneration in the cerebral cortex, histopathologically hallmarked by amyloid β (Aβ) extracellular plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. Correlation between these pathologic features and dementia has been challenged by the emergence of “nondemented with Alzheimer's neuropathology” (NDAN) individuals, cognitively intact despite displaying pathologic features of AD. The existence of these subjects suggests that some unknown mechanisms are triggered to resist Aβ-mediated detrimental events. Aβ accumulation affects mitochondrial redox balance, increasing oxidative stress status, which in turn is proposed as a primary culprit in AD pathogenesis. To clarify the relationship linking Aβ, oxidative stress, and cognitive impairment, we performed a comparative study on AD, NDAN, and aged-matched human postmortem frontal cortices of either sex. We quantitatively analyzed immunofluorescence distribution of oxidative damage markers, and of SOD2 (superoxide dismutase 2), PGC1α [peroxisome proliferator-activated receptor (PPAR) γ-coactivator 1α], PPARα, and catalase as key factors in antioxidant response, as well as the expression of miRNA-485, as a PGC1α upstream regulator. Our results confirm dramatic redox imbalance, associated with impaired antioxidant defenses in AD brain. By contrast, NDAN individuals display low oxidative damage, which is associated with high levels of scavenging systems, possibly resulting from a lack of PGC1α miRNA-485-related inhibition. Comparative analyses in neurons and astrocytes further highlighted cell-specific mechanisms to counteract redox imbalance. Overall, our data emphasize the importance of transcriptional and post-transcriptional regulation of antioxidant response in AD. This suggests that an efficient PGC1α-dependent “safety mechanism” may prevent Aβ-mediated oxidative stress, supporting neuroprotective therapies aimed at ameliorating defects in antioxidant response pathways in AD patients.