Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
Department of Clinical Biochemistry, Rigshospitalet, Glostrup, Denmark.
Mol Neurobiol. 2022 Dec;59(12):7495-7512. doi: 10.1007/s12035-022-03053-5. Epub 2022 Oct 6.
Disruptions of brain energy and neurotransmitter metabolism are associated with several pathological conditions including neurodegenerative diseases such as Alzheimer's disease. Transgenic rodent models, and in vitro preparations hereof, are often applied for studying pathological aspects of brain metabolism. However, despite the conserved cerebral development across mammalian species, distinct differences in cellular composition and structure may influence metabolism of the rodent and human brain. To address this, we investigated the metabolic function of acutely isolated brain slices and non-synaptic mitochondria obtained from the cerebral cortex of mice and neurosurgically resected neocortical tissue of humans. Utilizing dynamic isotope labeling with C-enriched metabolic substrates, we show that metabolism of glucose, acetate, β-hydroxybutyrate, and glutamine operates at lower rates in human cerebral cortical slices when compared to mouse slices. In contrast, human cerebral cortical slices display a higher capacity for converting exogenous glutamate into glutamine, which subsequently supports neuronal GABA synthesis, whereas mouse slices primarily convert glutamate into aspartate. In line with the reduced metabolic rate of the human brain slices, isolated non-synaptic mitochondria of the human cerebral cortex have a lower oxygen consumption rate when provided succinate as substrate. However, when provided pyruvate and malate, human mitochondria display a higher coupled respiration and lower proton leak, signifying a more efficient mitochondrial coupling compared to mouse mitochondria. This study reveals key differences between mouse and human brain metabolism concerning both neurons and astrocytes, which must be taken into account when applying in vitro rodent preparations as a model system of the human brain.
脑能量和神经递质代谢的紊乱与多种病理状况有关，包括神经退行性疾病，如阿尔茨海默病。转基因啮齿动物模型及其体外制剂通常用于研究脑代谢的病理方面。然而，尽管哺乳动物的大脑发育具有保守性，但细胞组成和结构的明显差异可能会影响啮齿动物和人类大脑的代谢。为了解决这个问题，我们研究了从小鼠大脑皮层中急性分离的脑切片和非突触线粒体以及从神经外科切除的人类新皮层组织的代谢功能。利用 C 标记代谢底物的动态同位素标记，我们表明与小鼠切片相比，葡萄糖、醋酸盐、β-羟丁酸和谷氨酰胺在人类大脑皮层切片中的代谢率较低。相比之下，人类大脑皮层切片具有更高的将外源性谷氨酸转化为谷氨酰胺的能力，随后支持神经元 GABA 的合成，而小鼠切片主要将谷氨酸转化为天冬氨酸。与人类大脑切片代谢率降低相一致，当提供琥珀酸盐作为底物时，人类大脑皮层的分离非突触线粒体的耗氧量较低。然而，当提供丙酮酸和苹果酸时，人类线粒体显示出更高的偶联呼吸和更低的质子泄漏，这表明与小鼠线粒体相比，线粒体的偶联效率更高。这项研究揭示了关于神经元和星形胶质细胞的小鼠和人类大脑代谢之间的关键差异，在将体外啮齿动物制剂作为人类大脑的模型系统应用时，必须考虑到这些差异。
