Kochkina Ekaterina G, Plesneva Svetlana A, Vasilev Dmitrii S, Zhuravin Igor A, Turner Anthony J, Nalivaeva Natalia N
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Thorez av., St. Petersburg, 194223, Russia.
Biogerontology. 2015 Aug;16(4):473-84. doi: 10.1007/s10522-015-9569-9. Epub 2015 Mar 20.
Due to an increasing life expectancy in developing countries, cases of type 2 diabetes and Alzheimer's disease (AD) in the elderly are growing exponentially. Despite a causative link between diabetes and AD, general molecular mechanisms underlying pathogenesis of these disorders are still far from being understood. One of the factors leading to cell death and cognitive impairment characteristic of AD is accumulation in the brain of toxic aggregates of amyloid-β peptide (Aβ). In the normally functioning brain Aβ catabolism is regulated by a cohort of proteolytic enzymes including insulin-degrading enzyme (IDE) and their deficit with ageing can result in Aβ accumulation and increased risk of AD. The aim of this study was a comparative analysis of IDE expression in the brain structures involved in AD, as well as in peripheral organs (the liver and kidney) of rats, during natural ageing and after experimentally-induced diabetes. It was found that ageing is accompanied by a significant decrease of IDE mRNA and protein content in the liver (by 32 and 81%) and brain structures (in the cortex by 58 and 47% and in the striatum by 53 and 68%, respectively). In diabetic animals, IDE protein level was increased in the liver (by 36%) and in the striatum (by 42%) while in the brain cortex and hippocampus it was 20-30% lower than in control animals. No significant IDE protein changes were observed in the kidney of diabetic rats. These data testify that ageing and diabetes are accompanied by a deficit of IDE in the brain structures where accumulation of Aβ was reported in AD patients, which might be one of the factors predisposing to development of the sporadic form of AD in the elderly, and especially in diabetics.
由于发展中国家预期寿命的增加，老年人中2型糖尿病和阿尔茨海默病（AD）的病例呈指数增长。尽管糖尿病与AD之间存在因果联系，但这些疾病发病机制的一般分子机制仍远未被理解。导致AD特征性细胞死亡和认知障碍的因素之一是淀粉样β肽（Aβ）毒性聚集体在大脑中的积累。在正常功能的大脑中，Aβ分解代谢由一组蛋白水解酶调节，包括胰岛素降解酶（IDE），随着年龄增长其缺乏会导致Aβ积累并增加患AD的风险。本研究的目的是比较分析在自然衰老和实验性诱导糖尿病后，大鼠AD相关脑结构以及外周器官（肝脏和肾脏）中IDE的表达。结果发现，衰老伴随着肝脏（分别下降32%和81%）和脑结构（皮层分别下降58%和47%，纹状体分别下降53%和68%）中IDE mRNA和蛋白质含量的显著降低。在糖尿病动物中，肝脏（增加36%）和纹状体（增加42%）中的IDE蛋白水平升高，而大脑皮层和海马体中的IDE蛋白水平比对照动物低20 - 30%。在糖尿病大鼠的肾脏中未观察到显著的IDE蛋白变化。这些数据证明，衰老和糖尿病伴随着AD患者中报道有Aβ积累的脑结构中IDE的缺乏，这可能是老年人尤其是糖尿病患者易患散发性AD的因素之一。
