Tang Jason, Oliveros Alfredo, Jang Mi-Hyeon
Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA.
Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Int Neurourol J. 2019 Feb;23(Suppl 1):S5-10. doi: 10.5213/inj.1938036.018. Epub 2019 Feb 28.
Synapses are sites of high energy demand which are dependent on high levels of mitochondrial derived adenosine triphosphate. Mitochondria within synaptic structures are key for maintenance of functional neurotransmission and this critical biological process is modulated by energy metabolism, mitochondrial distribution, mitochondrial trafficking, and cellular synaptic calcium flux. Synapse loss is presumed to be an early yet progressive pathological event in Alzheimer disease (AD), resulting in impaired cognitive function and memory loss which is particularly prevalent at later stages of disease. Supporting evidence from AD patients and animal models suggests that pathological mitochondrial dynamics indeed occurs early and is highly associated with synaptic lesions and degeneration in AD neurons. This review comprehensively highlights recent findings that describe how synaptic mitochondria pathology involves dysfunctional trafficking of this organelle, to maladaptive epigenetic contributions affecting mitochondrial function in AD. We further discuss how these negative, dynamic alterations impact synaptic function associated with AD. Finally, this review explores how antioxidant therapeutic approaches targeting mitochondria in AD can further clinical research and basic science investigations to advance our in-depth understanding of the pathogenesis of AD.
突触是高能量需求的部位,依赖于高水平的线粒体衍生三磷酸腺苷。突触结构内的线粒体对于维持功能性神经传递至关重要,而这一关键生物学过程受到能量代谢、线粒体分布、线粒体运输以及细胞突触钙通量的调节。突触丧失被认为是阿尔茨海默病(AD)早期但渐进性的病理事件,导致认知功能受损和记忆丧失,这在疾病后期尤为普遍。来自AD患者和动物模型的支持性证据表明,病理性线粒体动力学确实在早期就出现,并且与AD神经元中的突触损伤和退化高度相关。本综述全面强调了最近的研究发现,这些发现描述了突触线粒体病理学如何涉及该细胞器的功能失调运输,以及对AD中线粒体功能产生影响的适应不良的表观遗传因素。我们进一步讨论这些负面的动态改变如何影响与AD相关的突触功能。最后,本综述探讨了针对AD中线粒体的抗氧化治疗方法如何能够推动临床研究和基础科学研究,以增进我们对AD发病机制的深入理解。