Impairment of mitochondrial biogenesis and mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD). However, the extent to which the impairment of mitochondrial biogenesis influences mitochondrial dysfunction at the onset and during progression of AD is still unclear. Our study demonstrated that the protein expression pattern of the transcription factor pCREB/CREB, together with the protein expression of PGC-1α, NRF1, and TFAM are all significantly reduced in early ages of 3xTg-AD mice. We also found reduced mRNA expression levels of PKAC-α, CREB, PGC-1α, NRF1, NRF2, and TFAM as early as 1 month-of-age, an age at which there was no significant Aβ oligomer deposition, suggesting that mitochondrial biogenesis is likely impaired in ages preceding the development of the AD pathology. In addition, there was a decrease in VDAC2 expression, which is related to mitochondrial content and mitochondrial function, as demonstrated by protein expression of complex IV, as well as complex II + III, and complex IV activities, at later ages in 3xTg-AD mice. These results suggest that the impairment in mitochondrial biogenesis signaling mediated by PGC-1α at early ages of the AD mice model likely resulted in mitochondrial dysfunction and manifestation of the AD pathology at later ages. Taken together, enhancing mitochondrial biogenesis may represent a potential pharmacological approach for the treatment of AD.

中文翻译：

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在阿尔茨海默病的 3xTg 小鼠模型中，PGC-1α 介导的线粒体生物发生的损害先于线粒体功能障碍和阿尔茨海默病的病理学。

线粒体生物发生和线粒体功能障碍的损害是阿尔茨海默病 (AD) 的一个突出特征。然而，线粒体生物发生的损害在多大程度上影响 AD 发病和进展过程中的线粒体功能障碍仍不清楚。我们的研究表明，在 3xTg-AD 小鼠的早期，转录因子 pCREB/CREB ​​的蛋白质表达模式以及 PGC-1α、NRF1 和 TFAM 的蛋白质表达均显着降低。我们还发现早在 1 个月大时 PKAC-α、CREB、PGC-1α、NRF1、NRF2 和 TFAM 的 mRNA 表达水平降低，此时没有明显的 Aβ 寡聚体沉积，这表明线粒体生物发生可能在 AD 病理学发展之前的年龄受损。此外，VDAC2 表达下降，这与线粒体含量和线粒体功能有关，如复合物 IV 的蛋白质表达，以及复合物 II + III 和复合物 IV 活性，在 3xTg-AD 小鼠的后期。这些结果表明，在 AD 小鼠模型的早期，PGC-1α 介导的线粒体生物发生信号受损可能导致线粒体功能障碍和后期 AD 病理学的表现。总之，增强线粒体生物发生可能代表治疗 AD 的潜在药理学方法。这些结果表明，在 AD 小鼠模型的早期，PGC-1α 介导的线粒体生物发生信号受损可能导致线粒体功能障碍和后期 AD 病理学的表现。总之，增强线粒体生物发生可能代表治疗 AD 的潜在药理学方法。这些结果表明，在 AD 小鼠模型的早期，PGC-1α 介导的线粒体生物发生信号受损可能导致线粒体功能障碍和后期 AD 病理学的表现。总之，增强线粒体生物发生可能代表治疗 AD 的潜在药理学方法。