Abstract：
Alzheimer\'s disease (AD) is the most prevalent form of dementia and is characterized by progressive neurodegeneration leading to severe cognitive, memory, and behavioral impairments. The onset of AD involves a complex interplay among various factors, including age, genetics, chronic inflammation, and impaired energy metabolism. Despite significant efforts, there are currently no effective therapies capable of modifying the course of AD, likely owing to an excessive focus on the amyloid hypothesis and a limited consideration of other intracellular pathways. In the present review, we emphasize the emerging concept of AD as a metabolic disease, where alterations in energy metabolism play a critical role in its development and progression. Notably, glucose metabolism impairment is associated with mitochondrial dysfunction, oxidative stress, Ca2+ dyshomeostasis, and protein misfolding, forming interconnected processes that perpetuate a detrimental self-feeding loop sustaining AD progression. Advanced glycation end products (AGEs), neurotoxic compounds that accumulate in AD, are considered an important consequence of glucose metabolism disruption, and glyceraldehyde (GA), a glycolytic intermediate, is a key contributor to AGEs formation in both neurons and astrocytes. Exploring the impact of GA-induced glucose metabolism impairment opens up exciting possibilities for creating an easy-to-handle in vitro model that recapitulates the early stage of the disease. This model holds great potential for advancing the development of novel therapeutics targeting various intracellular pathways implicated in AD pathogenesis. In conclusion, looking beyond the conventional amyloid hypothesis could lead researchers to discover promising targets for intervention, offering the possibility of addressing the existing medical gaps in AD treatment.
摘要：
阿尔茨海默病（AD）是痴呆的最常见形式，其特征是进行性神经变性导致严重的认知，记忆,和行为障碍。AD的发病涉及各种因素之间复杂的相互作用，包括年龄,遗传学,慢性炎症，和受损的能量代谢。尽管付出了巨大努力，目前还没有能够改变AD病程的有效疗法，可能是由于过度关注淀粉样蛋白假说和对其他细胞内途径的有限考虑。在本次审查中，我们强调AD作为一种代谢性疾病的新兴概念，能量代谢的改变在其发育和发展中起着关键作用。值得注意的是,葡萄糖代谢障碍与线粒体功能障碍有关，氧化应激，Ca2+代谢异常，和蛋白质错误折叠，形成相互关联的过程，使维持AD进展的有害的自我喂养循环永存。晚期糖基化终产物（AGEs），在AD中积累的神经毒性化合物，被认为是葡萄糖代谢中断的重要后果，和甘油醛（GA），糖酵解中间体，是神经元和星形胶质细胞中AGEs形成的关键因素。探索GA诱导的葡萄糖代谢障碍的影响为创建易于处理的体外模型开辟了令人兴奋的可能性，该模型概括了疾病的早期阶段。该模型在推进靶向涉及AD发病机制的各种细胞内途径的新型治疗方法的开发方面具有巨大潜力。超越传统的淀粉样蛋白假说可能会导致研究人员发现有希望的干预目标，提供了解决AD治疗中现有医学差距的可能性。
