Cai Jiachen, Chen Yan, She Yuzhu, He Xiaoxin, Feng Hu, Sun Huaiqing, Yin Mengmei, Gao Junying, Sheng Chengyu, Li Qian, Xiao Ming
Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China.
Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Brain Pathol. 2025 May;35(3):e13316. doi: 10.1111/bpa.13316. Epub 2024 Oct 26.
Mitochondrial dysfunction is a well-established hallmark of Alzheimer's disease (AD). Despite recent documentation of transcellular mitochondrial transfer, its role in the pathogenesis of AD remains unclear. In this study, we report an impairment of mitochondrial quality within the astrocytes and neurons of adult 5 × FAD mice. Following treatment with mitochondria isolated from aged astrocytes induced by exposure to amyloid protein or extended cultivation, cultured neurons exhibited an excessive generation of reactive oxygen species and underwent neurite atrophy. Notably, aerobic exercise enhanced mitochondrial quality by upregulating CD38 within hippocampal astrocytes of 5 × FAD mice. Conversely, the knockdown of CD38 diminished astrocytic-neuronal mitochondrial transfer, thereby abolishing the ameliorative effects of aerobic exercise on neuronal oxidative stress, β-amyloid plaque deposition, and cognitive dysfunction in 5 × FAD mice. These findings unveil an unexpected mechanism through which aerobic exercise facilitates the transference of healthy mitochondria from astrocytes to neurons, thus countering the AD-like progression.
线粒体功能障碍是阿尔茨海默病（AD）公认的一个特征。尽管最近有关于跨细胞线粒体转移的文献报道，但其在AD发病机制中的作用仍不清楚。在本研究中，我们报告了成年5×FAD小鼠星形胶质细胞和神经元内线粒体质量的受损情况。用从暴露于淀粉样蛋白诱导的衰老星形胶质细胞或延长培养中分离出的线粒体进行处理后，培养的神经元表现出活性氧的过度产生，并发生神经突萎缩。值得注意的是，有氧运动通过上调5×FAD小鼠海马星形胶质细胞内的CD38来提高线粒体质量。相反，敲低CD38会减少星形胶质细胞-神经元的线粒体转移，从而消除有氧运动对5×FAD小鼠神经元氧化应激、β-淀粉样斑块沉积和认知功能障碍的改善作用。这些发现揭示了一种意想不到的机制，即有氧运动促进健康线粒体从星形胶质细胞向神经元的转移，从而对抗类似AD的进展。
