Abnormalities in cellular metabolism are seen early in Alzheimer’s disease (AD). Astrocyte support for neuronal function has a high metabolic demand, and astrocyte glucose metabolism plays a key role in encoding memory. This indicates that astrocyte metabolic dysfunction might be an early event in the development of AD. In this paper we interrogate glycolytic and mitochondrial functional changes and mitochondrial structural alterations in patients’ astrocytes derived with a highly efficient direct conversion protocol. In astrocytes derived from patients with sporadic (sAD) and familial AD (fAD) we identified reductions in extracellular lactate, total cellular ATP and an increase in mitochondrial reactive oxygen species. sAD and fAD astrocytes displayed significant reductions in mitochondrial spare respiratory capacity, have altered mitochondrial membrane potential and a stressed mitochondrial network. A reduction in glycolytic reserve and glycolytic capacity is seen. Interestingly, glycolytic reserve, mitochondrial spare respiratory capacity and extracellular lactate levels correlated positively with neuropsychological tests of episodic memory affected early in AD. We identified a deficit in the glycolytic enzyme hexokinase 1 (HK1), and correcting this deficit improved the metabolic phenotype in sAD not fAD astrocytes. Importantly, the amount of HK1 at the mitochondria was shown to be reduced in sAD astrocytes, and not in fAD astrocytes. Overexpression of HK1 in sAD astrocytes increases mitochondrial HK1 levels. In fAD astrocytes HK1 levels were unaltered at the mitochondria after overexpression. This study highlights a clear metabolic deficit in AD patient-derived astrocytes and indicates how HK1, with its roles in both oxidative phosphorylation and glycolysis, contributes to this.

细胞代谢异常在阿尔茨海默病 (AD) 的早期就可见到。星形胶质细胞对神经元功能的支持有很高的代谢需求，而星形胶质细胞的葡萄糖代谢在编码记忆中起着关键作用。这表明星形胶质细胞代谢功能障碍可能是AD发展的早期事件。在本文中，我们研究了通过高效直接转换方案衍生的患者星形胶质细胞的糖酵解和线粒体功能变化以及线粒体结构改变。在散发性 AD (sAD) 和家族性 AD (fAD) 患者的星形胶质细胞中，我们发现细胞外乳酸、总细胞 ATP 减少，线粒体活性氧增加。 sAD 和 fAD 星形胶质细胞显示线粒体备用呼吸能力显着降低，改变了线粒体膜电位和应激的线粒体网络。发现糖酵解储备和糖酵解能力减少。有趣的是，糖酵解储备、线粒体备用呼吸能力和细胞外乳酸水平与 AD 早期受影响的情景记忆的神经心理学测试呈正相关。我们发现了糖酵解酶己糖激酶 1 (HK1) 的缺陷，纠正这种缺陷可以改善 sAD 而非 fAD 星形胶质细胞的代谢表型。重要的是，sAD 星形胶质细胞中线粒体 HK1 的量减少，而 fAD 星形胶质细胞中则没有。 sAD 星形胶质细胞中 HK1 的过度表达会增加线粒体 HK1 水平。在 fAD 星形胶质细胞中，线粒体中的 HK1 水平在过度表达后没有改变。 这项研究强调了 AD 患者来源的星形胶质细胞存在明显的代谢缺陷，并表明 HK1 在氧化磷酸化和糖酵解中的作用如何促成这一缺陷。