Department of Drug and Health Sciences, University of Catania, Catania 95125, Italy.
Institute of Crystallography, National Council of Research, Catania Unit, Catania 95126, Italy.
Aging (Albany NY). 2021 Jul 21;13(14):18033-18050. doi: 10.18632/aging.203330.
Research on cerebral glucose metabolism has shown that the aging brain experiences a fall of aerobic glycolysis, and that the age-related loss of aerobic glycolysis may accelerate Alzheimer's disease pathology. In the healthy brain, aerobic glycolysis, namely the use of glucose outside oxidative phosphorylation, may cover energy demand and increase neuronal resilience to stressors at once. Currently, the drivers of aerobic glycolysis in neurons are unknown. We previously demonstrated that synthetic monomers of β-amyloid protein (Aβ) enhance glucose uptake in neurons, and that endogenous Aβ is required for depolarization-induced glucose uptake in cultured neurons. In this work, we show that cultured cortical neurons increased aerobic glycolysis in response to the inhibition of oxidative phosphorylation by oligomycin or to a kainate pulse. Such an increase was prevented by blocking the endogenous Aβ tone and re-established by the exogenous addition of synthetic Aβ monomers. The activity of mitochondria-bound hexokinase-1 appeared to be necessary for monomers-stimulated aerobic glycolysis during oxidative phosphorylation blockade or kainate excitation. Our data suggest that, through Aβ release, neurons coordinate glucose uptake with aerobic glycolysis in response to metabolic stressors. The implications of this new finding are that the age-related drop in aerobic glycolysis and the susceptibility to Alzheimer's disease could be linked to factors interfering with release and functions of Aβ monomers.
脑葡萄糖代谢研究表明，衰老的大脑经历有氧糖酵解的下降，而与年龄相关的有氧糖酵解的丧失可能会加速阿尔茨海默病的病理进程。在健康的大脑中，有氧糖酵解，即氧化磷酸化以外的葡萄糖利用，可能同时满足能量需求并增加神经元对应激源的适应能力。目前，神经元中有氧糖酵解的驱动因素尚不清楚。我们之前的研究表明，β-淀粉样蛋白（Aβ）的合成单体可增强神经元中的葡萄糖摄取，内源性 Aβ是培养神经元去极化诱导的葡萄糖摄取所必需的。在这项工作中，我们发现培养的皮质神经元在受到寡霉素抑制氧化磷酸化或受到海人藻酸脉冲刺激时，会增加有氧糖酵解。这种增加可通过阻断内源性 Aβ 来预防，并且可通过添加合成 Aβ 单体来重新建立。线粒体结合的己糖激酶-1 的活性似乎是单体刺激氧化磷酸化阻断或海人藻酸兴奋时有氧糖酵解所必需的。我们的数据表明，通过 Aβ 的释放，神经元可协调葡萄糖摄取与有氧糖酵解，以应对代谢应激源。这一新发现的意义在于，与年龄相关的有氧糖酵解下降和对阿尔茨海默病的易感性可能与干扰 Aβ 单体释放和功能的因素有关。
