Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, the Netherlands; Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, Faculty of Medical Sciences, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Department of Molecular Pharmacology, Faculty of Science and Engineering, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, the Netherlands.
Biochim Biophys Acta Mol Cell Res. 2022 Oct;1869(10):119326. doi: 10.1016/j.bbamcr.2022.119326. Epub 2022 Jul 14.
Alzheimers disease (AD) is the main cause of dementia and it is defined by cognitive decline coupled to extracellular deposit of amyloid-beta protein and intracellular hyperphosphorylation of tau protein. Historically, efforts to target such hallmarks have failed in numerous clinical trials. In addition to these hallmark-targeted approaches, several clinical trials focus on other AD pathological processes, such as inflammation, mitochondrial dysfunction, and oxidative stress. Mitochondria and mitochondrial-related mechanisms have become an attractive target for disease-modifying strategies, as mitochondrial dysfunction prior to clinical onset has been widely described in AD patients and AD animal models. Mitochondrial function relies on both the nuclear and mitochondrial genome. Findings from omics technologies have shed light on AD pathophysiology at different levels (e.g., epigenome, transcriptome and proteome). Most of these studies have focused on the nuclear-encoded components. The first part of this review provides an updated overview of the mechanisms that regulate mitochondrial gene expression and function. The second part of this review focuses on evidence of mitochondrial dysfunction in AD. We have focused on published findings and datasets that study AD. We analyzed published data and provide examples for mitochondrial-related pathways. These pathways are strikingly dysregulated in AD neurons and glia in sex-, cell- and disease stage-specific manners. Analysis of mitochondrial omics data highlights the involvement of mitochondria in AD, providing a rationale for further disease modeling and drug targeting.
阿尔茨海默病（AD）是痴呆症的主要病因，其特征是认知能力下降，同时伴有细胞外淀粉样β蛋白沉积和细胞内tau 蛋白过度磷酸化。从历史上看，针对这些标志性特征的努力在许多临床试验中都失败了。除了这些针对标志性特征的方法外，还有一些临床试验专注于 AD 的其他病理过程，如炎症、线粒体功能障碍和氧化应激。线粒体及其相关机制已成为疾病修饰策略的一个有吸引力的目标，因为在 AD 患者和 AD 动物模型中，临床发病前的线粒体功能障碍已被广泛描述。线粒体功能依赖于核基因组和线粒体基因组。组学技术的研究结果揭示了 AD 在不同层面（例如，表观基因组、转录组和蛋白质组）的病理生理学。这些研究大多数都集中在核编码成分上。本综述的第一部分提供了对调节线粒体基因表达和功能的机制的最新概述。第二部分重点介绍了 AD 中线粒体功能障碍的证据。我们集中研究了已发表的研究 AD 的发现和数据集。我们分析了已发表的数据，并提供了与线粒体相关的途径的例子。这些途径在 AD 神经元和神经胶质细胞中以性别、细胞和疾病阶段特异性的方式被显著失调。线粒体组学数据的分析强调了线粒体在 AD 中的参与，为进一步的疾病建模和药物靶向提供了依据。
