Biochemistry Division, ICMR-National Institute of Nutrition, Hyderabad, India.
Biochemistry Division, ICMR-National Institute of Nutrition, Hyderabad, India.
Chem Biol Interact. 2022 Mar 1;355:109840. doi: 10.1016/j.cbi.2022.109840. Epub 2022 Jan 31.
Aging is a main risk factor for many diseases including neurodegenerative disorders. Numerous theories and mechanisms including accumulation of advanced glycation end products (AGEs) have been put forward in explaining brain aging. However, a focused study on the status of AGEs in the brain during progressive aging in connection with interrelated cellular processes like ubiquitin-proteasome system (UPS), unfolded protein response, autophagy-lysosome system and apoptosis is lacking. In this study, we investigated the levels of AGEs in the brain of 5-, 10-, 15- and 20-months old WNIN rats. Endoplasmic reticulum (ER) stress response, UPS components, autophagy flux, neurotrophic and presynaptic markers along with cell death markers were analyzed by immunoblotting. The neuronal architecture was analyzed by H&E and Nissl staining. The results demonstrated progressive accumulation of AGEs in the brain during aging. Adaptive ER stress response was observed by 10-months while maladaptive ER stress response was seen at 15- and 20-months of age along with impaired UPS and autophagy, and perturbations in neuronal growth factors. All these disturbances intensify with age to further exaggerate cell death mechanisms. There was a shrinkage of the cell size with aging and Congo-red staining revealed β-amyloid accumulation in higher ages. Together these results suggest that progressive accumulation of AGEs with aging in the brain may lead to neuronal damage by affecting ER homeostasis, UPS, autophagic flux, and neuronal growth factors.
衰老是许多疾病的主要风险因素，包括神经退行性疾病。为了解释大脑衰老，已经提出了许多理论和机制，包括晚期糖基化终产物（AGEs）的积累。然而，缺乏一项关于 AGEs 在大脑中进行性衰老过程中的状态的集中研究，以及与之相关的细胞过程，如泛素蛋白酶体系统（UPS）、未折叠蛋白反应、自噬溶酶体系统和细胞凋亡。在这项研究中，我们研究了 5、10、15 和 20 个月大的 WNIN 大鼠大脑中的 AGEs 水平。通过免疫印迹分析内质网（ER）应激反应、UPS 成分、自噬流、神经营养和突触前标记物以及细胞死亡标记物。通过 H&E 和尼氏染色分析神经元结构。结果表明，随着年龄的增长，AGEs 在大脑中逐渐积累。10 个月时观察到适应性 ER 应激反应，而 15 个月和 20 个月时观察到适应性 ER 应激反应，同时 UPS 和自噬受损，神经元生长因子紊乱。随着年龄的增长，所有这些干扰都会加剧，进一步加剧细胞死亡机制。随着年龄的增长，细胞大小会缩小，刚果红染色显示β-淀粉样蛋白在较高年龄时积累。这些结果表明，随着年龄的增长，AGEs 在大脑中的逐渐积累可能通过影响内质网稳态、UPS、自噬流和神经元生长因子导致神经元损伤。
