German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany; Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany; Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.
Mech Ageing Dev. 2021 Jul;197:111499. doi: 10.1016/j.mad.2021.111499. Epub 2021 May 11.
The decline of nicotinamide adenine dinucleotide (NAD+) levels is a hallmark of aging in multiple organisms and tissues, including the human brain. Hence, agents that increase intracellular NAD+ could have beneficial effects in aging and age-related neurodegenerative diseases. Disturbances in NAD+ metabolism have also been observed in Parkinson's disease (PD), supporting a link between neuronal bioenergetics failure and disease pathogenesis. Here, we review emerging findings revealing key roles for NAD+ and related metabolites in experimental models of dopaminergic neurodegeneration and in PD patients. We discuss how increased NAD+ levels might ameliorate disease phenotypes by restoring neuronal mitochondrial energy metabolism, promoting cellular proteostasis, and modulating the immune system. Finally, we describe ongoing clinical trials targeting NAD+ in PD and highlight the need for further investigations to better delineate the association between NAD+, brain aging and disease, and optimal strategies for efficiently and safely raising NAD+ levels. A more comprehensive understanding of the basic mechanisms linking NAD+, energy metabolism, and PD, and of the impact of life-long NAD+ targeting strategies, are critical to inform future clinical applications.
烟酰胺腺嘌呤二核苷酸 (NAD+) 水平的下降是多种生物体和组织（包括人类大脑）衰老的标志。因此，增加细胞内 NAD+的物质可能对衰老和与年龄相关的神经退行性疾病有有益的影响。NAD+ 代谢的紊乱也在帕金森病 (PD) 中观察到，这支持了神经元生物能量衰竭与疾病发病机制之间的联系。在这里，我们回顾了新兴的发现，这些发现揭示了 NAD+ 和相关代谢物在多巴胺能神经退行性变的实验模型中和 PD 患者中的关键作用。我们讨论了增加 NAD+ 水平如何通过恢复神经元线粒体能量代谢、促进细胞蛋白稳态和调节免疫系统来改善疾病表型。最后，我们描述了针对 PD 中 NAD+ 的正在进行的临床试验，并强调需要进一步研究以更好地区分 NAD+、大脑衰老和疾病之间的关联，以及有效和安全地提高 NAD+水平的最佳策略。更全面地了解将 NAD+、能量代谢和 PD 联系起来的基本机制，以及终身靶向 NAD+策略的影响，对于为未来的临床应用提供信息至关重要。
