Simon M. Bell, Hollie Wareing, Francesco Capriglia, Rachel Hughes, Katy Barnes, Alexander Hamshaw, Liam Adair, Allan Shaw, Alicja Olejnik, Suman De, Elizabeth New, Pamela J. Shaw, Matteo De Marco, Annalena Venneri, Daniel J. Blackburn, Laura Ferraiuolo, Heather Mortiboys
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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.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":null,"pages":null},"PeriodicalIF":9.6000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer’s disease astrocytes\",\"authors\":\"Simon M. Bell, Hollie Wareing, Francesco Capriglia, Rachel Hughes, Katy Barnes, Alexander Hamshaw, Liam Adair, Allan Shaw, Alicja Olejnik, Suman De, Elizabeth New, Pamela J. 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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. 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引用次数: 0
摘要
阿尔茨海默病(AD)早期就会出现细胞代谢异常。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记忆编码中起着关键作用。这表明星形胶质细胞代谢功能障碍可能是 AD 发病的早期事件。在本文中,我们通过高效的直接转换方案研究了患者星形胶质细胞中糖酵解和线粒体功能的变化以及线粒体结构的改变。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、细胞总 ATP 减少,线粒体活性氧增加。sAD 和 fAD 星形胶质细胞的线粒体剩余呼吸能力显著降低,线粒体膜电位改变,线粒体网络受压。糖酵解储备和糖酵解能力也有所下降。有趣的是,糖酵解储备、线粒体剩余呼吸能力和细胞外乳酸水平与影响早期记忆力的神经心理学测试呈正相关。我们发现糖酵解酶己糖激酶 1(HK1)存在缺陷,纠正这种缺陷可改善 sAD 而非 fAD 星形胶质细胞的代谢表型。重要的是,在 sAD 星形胶质细胞中,线粒体中的 HK1 数量减少了,而在 fAD 星形胶质细胞中没有减少。在 sAD 星形胶质细胞中过表达 HK1 会增加线粒体 HK1 的水平。在 fAD 星形胶质细胞中,过表达后线粒体中的 HK1 水平没有变化。这项研究强调了 AD 患者来源的星形胶质细胞中存在明显的代谢缺陷,并指出了 HK1 在氧化磷酸化和糖酵解中的作用是如何导致这一缺陷的。
Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer’s disease astrocytes
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.
期刊介绍:
Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.