Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
J Alzheimers Dis. 2024;100(s1):S363-S385. doi: 10.3233/JAD-240787.
More than a century after the first description of Alzheimer's disease (AD), the road to a cure for this complex and heterogeneous neurodegenerative disorder has been paved by countless descriptive hypotheses and successive clinical trial failures. Auspiciously, the era of genome-wide association studies revolutionized the classical "neurocentric" view of AD by providing clues that brain-resident immune cells (i.e., microglia and astrocytes) are also key players in the pathological and clinical trajectory of this neurodegenerative disorder. Considering that the intercommunication among neurons, astrocytes, and microglia is fundamental for the functional organization of the brain, it is evident that the disruption of the proper functioning of this "triad" could contribute to the neuroinflammatory and neurodegenerative events that occur in the AD brain. Importantly, recent scientific progress in the burgeoning field of immunometabolism, a crossroad between metabolism and immune response, shed light on the importance of metabolic reprogramming of brain-resident immune cells in AD pathology. In this sense, the present review is aimed to summarize and discuss the current knowledge on the metabolic patterns of brain-resident immune cells during the AD continuum, putting a special focus on glucose, amino acids, and lipid metabolism. Changing the "old" picture of AD pathological basis by integrating the role of brain-resident immune cells it is imperative to establish new and feasible therapeutic interventions able to curb neuroinflammatory and neurodegenerative processes, and consequently cognitive deterioration.
在首次描述阿尔茨海默病（AD）一个多世纪后，无数描述性假说和连续的临床试验失败为治愈这种复杂且异质的神经退行性疾病铺平了道路。幸运的是，全基因组关联研究的时代通过提供线索彻底改变了 AD 的经典“神经中心”观点，这些线索表明，驻留于大脑中的免疫细胞（即小胶质细胞和星形胶质细胞）也是这种神经退行性疾病的病理和临床轨迹中的关键参与者。鉴于神经元、星形胶质细胞和小胶质细胞之间的相互交流对于大脑的功能组织至关重要，因此，这种“三联体”的正常功能的破坏可能会导致 AD 大脑中发生神经炎症和神经退行性事件。重要的是，免疫代谢学这一新兴领域的最近科学进展（代谢与免疫反应的交叉点）揭示了驻留于大脑中的免疫细胞的代谢重编程在 AD 病理中的重要性。从这个意义上说，本综述旨在总结和讨论 AD 连续体期间驻留于大脑中的免疫细胞的代谢模式的现有知识，特别关注葡萄糖、氨基酸和脂质代谢。通过整合驻留于大脑中的免疫细胞的作用来改变 AD 病理基础的“旧”图景，对于建立新的可行的治疗干预措施来抑制神经炎症和神经退行性过程，从而阻止认知能力下降至关重要。
