Linking Defects in DNA Repair to Mitochondrial Dysfunction in Alzheimer's Disease

阿尔茨海默病（AD）是一种破坏性的神经系统疾病，与认知功能的进行性丧失以及身体和精神技能的进行性丧失有关。我们和其他人已经观察到，在包括AD在内的几种人类病理条件下，DNA修复缺陷与线粒体功能障碍相关。还有强有力的证据表明，线粒体功能障碍有助于AD的突出神经病理学特征，并且高水平的氧化应激和DNA损伤在AD患者的脑神经元中积累。此外，现在广泛接受的是，持续的DNA损伤导致聚（ADP-核糖）聚合酶-1（PARP 1）的慢性激活，这进而触发一系列下游事件，包括烟酰胺腺嘌呤二核苷酸（NAD+）的耗尽、Sirtuins的抑制和改变的细胞生物能量学。PARP 1在AD患者的神经元中被过度激活，并且抑制PARP 1或增加NAD+的药剂部分逆转AD细胞模型中的表型变化。重要的是，我们最近已经表明，NAD+的消耗及其随后的补充可以改变AD病理学的关键方面，如tau磷酸化和DNA损伤积累。基于这些观察结果，我们建议，调查AD病理，NAD+持续耗竭，线粒体自噬缺陷，线粒体功能障碍，改变或有缺陷的DNA修复之间的复杂关系。

Alzheimers disease (AD) is a devastating neurological disease associated with progressive loss of cognitive function as well as progressive loss of physical and mental skills. We and others have observed that defects in DNA repair correlate with mitochondrial dysfunction in the context of several human pathological conditions, including AD. There is also strong evidence that mitochondrial dysfunction contributes to prominent neuropathological features of AD and that high levels of oxidative stress and DNA damage accumulate in brain neurons from AD patients. Furthermore, it is now widely-accepted that persistent DNA damage leads to chronic activation of poly (ADP-ribose) polymerase-1 (PARP1), which in turn triggers a series of downstream events including depletion of nicotinamide adenine dinucleotide (NAD+), inhibition of Sirtuins, and altered cellular bioenergetics. PARP1 is hyper-activated in neurons of AD patients and agents that inhibit PARP1 or increase NAD+ partially reverse phenotypic changes in cellular models of AD. Importantly, we have recently shown that depletion of NAD+ and its subsequent replenishment can alter critical aspects of AD pathology like tau phosphorylation and DNA damage accumulation. Based on these observations, we propose to, investigate the complex relationships between AD pathology, persistent depletion of NAD+, defective mitophagy, mitochondrial dysfunction, and altered or defective DNA repair.