Abstract：
Neuroinflammation is a prominent feature of Alzheimer\'s disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.
摘要：
神经炎症是阿尔茨海默病(AD)的突出特征。活化的小胶质细胞经历细胞代谢的重编程,这在疾病期间为其细胞活动提供动力。因此，小胶质细胞免疫代谢的选择性靶向可能对AD的治疗有益.在AD大脑中,小胶质细胞己糖激酶2（HK2）的水平，一种通过促进糖酵解来支持炎症反应的酶，显著增加。此外,HK2显示出非代谢活性，将其炎症作用扩展到糖酵解之外。HK2的拮抗作用以基因剂量依赖性方式影响小胶质细胞表型和疾病进展。HK2完全丢失无法通过加剧炎症来改善病理，而其单倍体不足降低5xFAD小鼠的病理学。我们认为HK2的部分拮抗作用是通过调节NF-κB信号通过其细胞溶质靶标有效减缓疾病进展。IKBα.HK2的完全丧失影响与线粒体功能障碍相关的其他炎症机制。
