AD认知功能障碍的代谢紊乱机制:脑胰岛素抵抗及其介导的PI3K/Akt信号通路受损

阿尔茨海默病(Alzheimer’s disease, AD)是一种以进行性痴呆为主要特征的中枢神经系统退行性疾病,其认知功能障碍可能与Ⅱ型糖尿病(type 2 diabetes, T2DM)诱发的胰岛素抵抗所损伤的PI3K/Akt胰岛素信号级联通路相关。胰岛素是调节机体新陈代谢的重要激素,通过与神经细胞表面的胰岛素受体结合激活PI3K/Akt信号通路,以调控葡萄糖、脂质的代谢。任何中间媒介功能紊乱所导致的脑胰岛素水平和胰岛素敏感性的降低都会损坏PI3K/Akt信号通路,诱发脑能量代谢障碍、Aβ沉积、Tau蛋白过度磷酸化,引起并加重AD认知功能障碍。因此,本文以PI3K/Akt胰岛素信号通路为主线,揭示了T2DM中脑胰岛素抵抗(insulin resistance, IR)与AD之间的复杂机制,旨在加深对脑IR介导的AD病理过程的系统性理解,借此为延缓或治疗AD的认知功能障碍提供理论基础。

Metabolic disorder mechanisms of cognitive dysfunction in AD: brain insulin resistance and impairment of the PI3K/Akt signaling pathway

Alzheimer’s disease(AD) is a central nervous system degenerative disease characterized by progressive dementia, and its cognitive dysfunction may be associated with the PI3 K/Akt signaling cascade of insulin resistance damaged by type 2 diabetes(T2 DM). Insulin is an important hormone regulating the metabolism of the body, which can be bind to the insulin receptor on the surface of nerve cells, thereby activating the PI3 K/Akt signaling cascade to regulate the glucose and lipids metabolism. Decreased brain insulin level and insulin sensitivity caused by dysfunction of intermediate media, can damage the PI3 K/Akt signaling cascade and induce cerebral energy metabolism dysfunction, Aβ deposition, Tau protein hyperphosphorylation, and cognitive function impairment of AD. This review will reveal the complex molecular mechanisms among the brain insulin resistance(IR) in T2 DM, PI3 K/Akt insulin signaling cascade and AD for better systematic understanding of brain IR-mediated AD pathological process, thereby to provide important theoretical basis for delaying and treatment of the cognitive dysfunction of AD.