糖酵解作为神经退行性疾病的核心病理轴

摘要(中文译文)

糖酵解在神经退行性疾病中日益被认为是一种病理核心机制，而不仅仅是伴随现象。本文首先阐述了大脑中神经元、星形胶质细胞、小胶质细胞和少突胶质细胞之间的代谢分工，特别强调细胞类型特异性的糖酵解通量、乳酸穿梭以及脑-外周能量代谢整合框架。随后系统比较了阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化（ALS）、威尔逊病（WD）、亨廷顿病（HD）和多发性硬化（MS）中葡萄糖摄取、糖酵解中间产物和乳酸代谢的改变，突出显示了不同细胞类型、疾病阶段和脑区之间的显著异质性。这些代谢紊乱不仅包括全脑低代谢和能量危机，还涉及星形胶质细胞和小胶质细胞中代偿性糖酵解增强和炎症相关代谢重编程，并进一步延伸至涉及外周血细胞、肌肉和肝脏的系统性代谢表型。本文总结了近年来用于表征糖酵解重编程的方法学进展，包括氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）、超极化碳-13磁共振波谱（¹³C-MRS）、代谢组学、单细胞和空间转录组学、基因编码代谢传感器以及Seahorse检测。此外，还讨论了潜在的治疗策略，重点关注6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3（PFKFB3）、星形胶质细胞-神经元乳酸穿梭（ANLS）、小胶质细胞糖酵解和乳酸化等靶点，以及系统性代谢调节和纳米递送方法。最后，强调了关键挑战，包括因果关系不明确、双相和细胞类型特异性效应、脑-外周整合不足以及缺乏标准化指标，指出需要纵向、多模态和阶段特异性策略，以将糖酵解重新定位为神经退行性疾病中可靶向的治疗维度。

Abstract

Glycolysis is increasingly recognized as a pathological backbone in neurodegenerative diseases rather than merely an accompanying epiphenomenon. This article first delineates the division of metabolic labor among neurons, astrocytes, microglia, and oligodendrocytes in the brain, with particular emphasis on cell type-specific glycolytic flux, lactate shuttling, and an integrated brain-periphery framework of energy metabolism. It then systematically compares alterations in glucose uptake, glycolytic intermediates, and lactate metabolism across Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Wilson disease (WD), Huntington's disease (HD), and multiple sclerosis (MS), highlighting pronounced heterogeneity across cell types, disease stages, and brain regions. These metabolic disturbances encompass not only global cerebral hypometabolism and an energy crisis, but also compensatory hyperglycolysis and inflammation-associated metabolic reprogramming in astrocytes and microglia, and extend further to systemic metabolic phenotypes involving peripheral blood cells, muscle, and liver. The article summarizes recent methodological advances for characterizing glycolytic reprogramming, including fluorodeoxyglucose positron emission tomography (FDG-PET), hyperpolarized carbon-13 magnetic resonance spectroscopy(ˆ13C-MRS), metabolomics, single-cell and spatial transcriptomics, genetically encoded metabolic sensors, and Seahorse assays. In addition, potential therapeutic strategies are discussed, focusing on targets such as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3(PFKFB3), the astrocyte-neuron lactate shuttle (ANLS), microglial glycolysis and lactylation, as well as systemic metabolic modulation and nanodelivery approaches. Finally, key challenges are highlighted, including unclear causal relationships, biphasic and cell type-specific effects, insufficient brain-periphery integration, and the lack of standardized metrics, underscoring the need for longitudinal, multimodal, and stage-specific strategies to reposition glycolysis as a targetable therapeutic dimension in neurodegenerative diseases.

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