Keskinoz Elif Nedret, Celik Musa, Toklucu Ezgi Sila, Birisik Kerem, Erisir Alev, Oz-Arslan Devrim
Department of Anatomy, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Kayisdagi Cad. No. 32, Atasehir, Istanbul, Turkey.
Institute of Health Science, Department of Anatomy, Acibadem Mehmet Ali Aydinlar University, Kayisdagi Cad. No. 32, Atasehir, Istanbul, Turkey.
Mol Neurobiol. 2025 Jun;62(6):7075-7092. doi: 10.1007/s12035-024-04632-4. Epub 2024 Dec 11.
Mitochondrial dysfunction is increasingly recognized as a key factor in Alzheimer's disease (AD) pathogenesis, but the precise relationship between mitochondrial dynamics and proteinopathies in AD remains unclear. This study investigates the role of mitochondrial dynamics and function in the hippocampal tissue and peripheral blood mononuclear cells (PBMCs) of 5xFAD transgenic mice, as a model of AD. The levels of mitochondrial fusion proteins OPA1 and MFN2 and fission proteins DRP1 and phospho-DRP1 (S616) at 3, 6, and 9 months of age were assessed. Western blot analysis revealed significantly lower levels of OPA1 and MFN2 in the hippocampus of 6- and 9-month-old transgenic (TG) 5xFAD mice compared to controls (CTR), while DRP1 and pDRP1 levels were increased in 9-month-old TG mice. Additionally, MFN2 were decreased in the PBMCs of 9-month-old TG mice, indicating systemic mitochondrial alterations. Ultrastructural analysis of hippocampal tissues showed substantial alterations in mitochondrial morphology, including abnormalities in size and shape, a preponderance of teardrop-shaped mitochondria, and alterations in the somatic mitochondria-ER complex. Notably, mitochondria-associated ER contact sites were more distant in TG mice, suggesting functional impairments. Flow cytometric measurements demonstrated decreased mitochondrial membrane potential and mass, along with increased superoxide production, in the PBMCs of TG mice, particularly at 9 months, highlighting compromised mitochondrial function. Levels of key mitochondrial proteins including VDAC, TOM2O, and mitophagy-related protein PINK1 levels altered in both central and peripheral tissue of TG mice. These findings suggest that mitochondrial dysfunction and altered dynamics are early events in AD development in 5xFAD mice, manifesting in both central and peripheral tissues, and support the notion that mitochondrial abnormalities are an integral component of AD pathology. These insights might lead to the development of targeted therapies that modulate mitochondrial dynamics and function to mitigate AD progression.
线粒体功能障碍日益被认为是阿尔茨海默病（AD）发病机制中的一个关键因素，但线粒体动力学与AD中蛋白质病的确切关系仍不清楚。本研究以AD模型5xFAD转基因小鼠为研究对象，探讨线粒体动力学和功能在其海马组织和外周血单核细胞（PBMC）中的作用。评估了3、6和9月龄时线粒体融合蛋白OPA1和MFN2以及裂变蛋白DRP1和磷酸化DRP1（S616）的水平。蛋白质印迹分析显示，与对照组（CTR）相比，6月龄和9月龄转基因（TG）5xFAD小鼠海马中OPA1和MFN2的水平显著降低，而9月龄TG小鼠中DRP1和pDRP1的水平升高。此外，9月龄TG小鼠的PBMC中MFN2减少，表明全身线粒体发生改变。海马组织的超微结构分析显示线粒体形态有大量改变，包括大小和形状异常、泪滴状线粒体占优势以及体细胞线粒体-内质网复合体改变。值得注意的是，TG小鼠中线粒体相关内质网接触位点更远，提示功能受损。流式细胞术测量显示，TG小鼠的PBMC中线粒体膜电位和质量降低，同时超氧化物产生增加，尤其是在9月龄时，突出了线粒体功能受损。包括电压依赖性阴离子通道（VDAC）、外膜转位酶20（TOM2O）和线粒体自噬相关蛋白PINK1在内的关键线粒体蛋白水平在TG小鼠的中枢和外周组织中均发生改变。这些发现表明，线粒体功能障碍和动力学改变是5xFAD小鼠AD发展过程中的早期事件，在中枢和外周组织中均有表现，并支持线粒体异常是AD病理学一个不可或缺组成部分的观点。这些见解可能会导致开发出有针对性的疗法，调节线粒体动力学和功能以减轻AD进展。
