Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Basic Neuroscience Division, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Sci Rep. 2017 Oct 25;7(1):14038. doi: 10.1038/s41598-017-14420-x.
Body-wide changes in bioenergetics, i.e., energy metabolism, occur in normal aging and disturbed bioenergetics may be an important contributing mechanism underlying late-onset Alzheimer's disease (LOAD). We investigated the bioenergetic profiles of fibroblasts from LOAD patients and healthy controls, as a function of age and disease. LOAD cells exhibited an impaired mitochondrial metabolic potential and an abnormal redox potential, associated with reduced nicotinamide adenine dinucleotide metabolism and altered citric acid cycle activity, but not with disease-specific changes in mitochondrial mass, production of reactive oxygen species, transmembrane instability, or DNA deletions. LOAD fibroblasts demonstrated a shift in energy production to glycolysis, despite an inability to increase glucose uptake in response to IGF-1. The increase of glycolysis and the abnormal mitochondrial metabolic potential in LOAD appeared to be inherent, as they were disease- and not age-specific. Our findings support the hypothesis that impairment in multiple interacting components of bioenergetic metabolism may be a key mechanism contributing to the risk and pathophysiology of LOAD.
全身范围内生物能量学（即能量代谢）的变化发生在正常衰老过程中，而生物能量学的紊乱可能是导致迟发性阿尔茨海默病（LOAD）的一个重要致病机制。我们研究了 LOAD 患者和健康对照者成纤维细胞的生物能量学特征，作为年龄和疾病的函数。LOAD 细胞表现出受损的线粒体代谢潜能和异常的氧化还原潜能，与烟酰胺腺嘌呤二核苷酸代谢减少和柠檬酸循环活性改变有关，但与线粒体质量、活性氧产生、跨膜不稳定性或 DNA 缺失的疾病特异性变化无关。尽管 LOAD 成纤维细胞对 IGF-1 没有增加葡萄糖摄取的反应，但它们表现出向糖酵解的能量产生转移。LOAD 中糖酵解的增加和异常的线粒体代谢潜能似乎是内在的，既不是疾病特异性的，也不是年龄特异性的。我们的研究结果支持这样一种假设，即生物能量代谢多个相互作用成分的损伤可能是导致 LOAD 风险和病理生理学的关键机制。
