Hippocampal neuronal damage likely underlies cognitive impairment in vascular dementia (VaD). PPARγ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. However, the role and the precise mechanism of how PGC-1α alleviates hippocampal neuronal injury remain unknown. To address this question, HT-22 cells, an immortalized hippocampal neuron cell line, with or without PGC-1α overexpression were subjected to oxygen-glucose deprivation (OGD), which mimics the circumstance of chronic cerebral hypoperfusion in VaD. After OGD, cell viability was assessed using the MTS assay. The mitochondrial function and reactive oxygen species (ROS) were both detected. ChIP-Seq analysis was employed to discover the underlying molecular mechanism of PGC-1α-mediated neuroprotective effects. Our results showed that mitochondrial membrane potentials were increased and ROS production was decreased in PGC-1α overexpressing cells, which increased cell viability. The further bioinformatics analysis from ChIP-Seq data indicated that PGC-1α may participate in the regulation of apoptosis, autophagy, and mitophagy pathways in HT-22 cells. We found that PGC-1α promoted the LC3-II formation and reduced the neuronal apoptosis determined by TUNEL staining. In addition, PGC-1α upregulated the expressions of mitochondrial antioxidants, including SOD2, Trx2, and Prx3. In summary, our findings indicate that PGC-1α may attenuate OGD-induced hippocampal neuronal damage by regulating multiple mechanisms, like autophagy and mitochondrial function. Thus, PGC-1α may be a potential therapeutic target for hippocampal damage associated with cognitive impairment.

中文翻译：

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PGC-1α的上调减轻氧 - 葡萄糖剥夺诱导的海马神经元损伤

海马神经元损伤可能是血管性痴呆 (VaD) 认知障碍的基础。PPAR γ coactivator-1 α (PGC-1 α ) 是线粒体生物发生的主要调节剂。然而，PGC- 1α如何减轻海马神经元损伤的作用和确切机制仍然未知。为了解决这个问题，HT-22 细胞，一种永生化的海马神经元细胞系，有或没有 PGC-1 α过度表达受到氧-葡萄糖剥夺 (OGD) 的影响，这模拟了 VaD 中慢性脑灌注不足的情况。在 OGD 之后，使用 MTS 测定法评估细胞活力。线粒体功能和活性氧（ROS）均被检测到。ChIP-Seq 分析用于发现 PGC-1 α介导的神经保护作用的潜在分子机制。我们的研究结果表明，过表达 PGC-1 α的细胞中线粒体膜电位增加，ROS 产生减少，这增加了细胞活力。来自 ChIP-Seq 数据的进一步生物信息学分析表明，PGC-1 α可能参与 HT-22 细胞凋亡、自噬和线粒体自噬途径的调节。我们发现 PGC-1α促进 LC3-II 形成并减少由 TUNEL 染色确定的神经元凋亡。此外，PGC-1 α上调线粒体抗氧化剂的表达，包括 SOD2、Trx2 和 Prx3。总之，我们的研究结果表明，PGC-1 α可能通过调节多种机制（如自噬和线粒体功能）来减轻 OGD 诱导的海马神经元损伤。因此，PGC-1 α可能是与认知障碍相关的海马损伤的潜在治疗靶点。