Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
Pharmacol Res. 2020 Sep;159:104948. doi: 10.1016/j.phrs.2020.104948. Epub 2020 May 22.
Impaired neuronal proteostasis is a salient feature of both aging and protein misfolding disorders. Amyloidosis, a consequence of this phenomena is observed in the brains of diabetic patients over the chronic time period. These toxic aggregates not only cause age-related decline in proteostasis, but also dwindle its ability to increase or restore the chaperones in response to any stressful condition. Mitochondria acts as the main source of energy regulation and many metabolic disorders such as diabetes have been associated with altered oxidative phosphorylation (OxPhos) and redox imbalance in the mitochondria. The mitochondrial unfolded protein response (UPR) acts as a mediator for maintaining the mitochondrial protein homeostasis and quality control during such conditions. Over a long time period, these responses start shutting off leading to proteotoxic stress in the neurons. This reduces the buffering capacity of protein network signalling during aging, thereby increasing the risk of neurodegeneration in the brain. In this review, we focus on the proteotoxic stress that occurs as an amalgamation of diabetes and aging, as well as the impact of mitochondrial dysfunction on the neuronal survival affecting the diabetic brain and its long term consequences on the memory changes.
神经元稳态失衡是衰老和蛋白质错误折叠疾病的一个显著特征。淀粉样变性是这一现象的结果，在慢性糖尿病患者的大脑中可以观察到。这些有毒聚集体不仅导致与年龄相关的蛋白质稳态下降，而且使其增加或恢复伴侣蛋白以应对任何应激条件的能力下降。线粒体是能量调节的主要来源，许多代谢紊乱，如糖尿病，与线粒体氧化磷酸化（OxPhos）和氧化还原失衡的改变有关。线粒体未折叠蛋白反应（UPR）作为一种介质，在这种情况下维持线粒体蛋白质稳态和质量控制。随着时间的推移，这些反应开始关闭，导致神经元中的蛋白质毒性应激。这会降低衰老过程中蛋白质网络信号的缓冲能力，从而增加大脑神经退行性变的风险。在这篇综述中，我们重点讨论了糖尿病和衰老共同作用引起的蛋白质毒性应激，以及线粒体功能障碍对神经元存活的影响，从而影响糖尿病大脑及其对记忆变化的长期影响。
