PDF(Pubmed)
Abstract：
Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer\'s disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff\'s base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease\'s pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin\'s role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid β peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aβ build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.
摘要：
晚期糖基化终产物（AGEs）在大脑中积累，导致神经退行性疾病，如阿尔茨海默病（AD）。AD的病理生理学受AGEs受体和toll样受体4(TLR4)的影响。蛋白质糖基化通过一系列涉及席夫碱形成的复杂反应导致不可逆的AGEs，Amadori的反应,接着是美拉德反应,导致大脑葡萄糖代谢异常，氧化应激，线粒体功能失调,斑块沉积，和神经元死亡。淀粉样斑块和其他刺激激活巨噬细胞，它们是AD发展中至关重要的免疫细胞，引发炎症分子的产生，并有助于疾病的发病机制。动脉粥样硬化的危险因素使AD的风险增加一倍，痴呆症,高龄,和2型糖尿病（DM）。随着年龄的增长,由于乙二醛酶水平的降低和AGE积累的增加,神经系统疾病如AD的患病率增加。胰岛素在蛋白质稳定中的作用影响AD样tau磷酸化和淀粉样β肽清除的标志，影响脂质代谢，炎症,血管反应性，和血管功能。高迁移率族蛋白1（HMGB1），神经炎症反应的关键引发剂和激活剂，与AD等神经退行性疾病的发展有关。发现TLR4抑制剂可改善记忆和学习障碍并减少Aβ积累。抗糖基化药物的治疗研究，晚期糖基化终产物受体（RAGE）抑制剂，和年龄破坏者为干预策略提供了希望。饮食和生活方式的改变也可以减缓AD的进展。需要针对AGE相关途径的较新的治疗方法。
