Zhang Xin, Alshakhshir Nadine, Zhao Liqin
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, United States.
Neuroscience Graduate Program, University of Kansas, Lawrence, KS, United States.
Front Neurosci. 2021 Apr 28;15:662242. doi: 10.3389/fnins.2021.662242. eCollection 2021.
Alzheimer's disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene - - that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.
阿尔茨海默病（AD）是与年龄相关的痴呆最常见的形式。尽管经过数十年的研究，但AD的病因和发病机制仍未完全明确。脑葡萄糖代谢减退长期以来一直被认为是AD临床前期出现的一个显著异常。最近的研究表明，糖酵解代谢，即葡萄糖在细胞质中的分解途径，可能在AD的发展中起关键作用。糖酵解对于大脑中的各种神经活动至关重要，包括能量产生、突触传递和氧化还原稳态。在临床前期和临床AD患者中，糖酵解通量降低均已显示与淀粉样蛋白和tau病理的严重程度相关。此外，在AD患者大脑中发现的葡萄糖积累增加支持了糖酵解缺陷可能是这种表型发展的一个促成因素的假说。脑高血糖也为AD与糖尿病之间有充分记录的联系提供了一个合理的解释。人类拥有载脂蛋白E（ApoE）基因的三种主要变体，它们赋予对AD不同的易感性。最近的研究结果表明，神经元糖酵解受到人类ApoE异构体的显著影响，糖酵解稳健性可能是使携带ApoE2的大脑对AD的神经退行性风险更具抵抗力的主要机制。除了AD之外，在其他神经退行性疾病中也观察到了糖酵解功能障碍，包括帕金森病、亨廷顿病和肌萎缩侧索硬化症，这强化了糖酵解功能障碍是导致神经退行性变的共同途径这一概念。综上所述，这些进展突出了一个有前景的转化机会，即通过靶向糖酵解来增强脑代谢弹性，从而改变脑衰老或疾病发展进程，以预防或降低不仅是AD还有其他神经退行性疾病的风险。
