Department of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
Panminerva Med. 2012 Sep;54(3):171-8.
Herein, we review evidence that systemic insulin-resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Insulin-resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and endoplasmic reticulum (ER) stress. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues, e.g. liver, get released into peripheral blood, and subsequently transit across the blood-brain barrier into the brain where they induce brain insulin-resistance, inflammation, and cell death (extrinsic pathway). These abnormalities establish or help propagate a cascade of neurodegeneration associated with increased ER stress and ceramide generation, which exacerbate brain insulin-resistance, cell death, myelin degeneration, and neuro-inflammation. The data suggest that a mal-signaling network mediated by toxic ceramides, ER stress, and insulin-resistance should be targeted to disrupt positive feedback loops that drive the AD neurodegeneration cascade.
在这里，我们回顾了与肥胖、2 型糖尿病和非酒精性脂肪性肝炎相关的系统性胰岛素抵抗疾病促进神经退行性变的证据。胰岛素抵抗会扰乱脂质代谢，促进神经酰胺积累，并伴有炎症和内质网（ER）应激。从机制上讲，我们提出在中枢神经系统外组织（如肝脏）产生的有毒神经酰胺会被释放到外周血液中，并随后穿过血脑屏障进入大脑，在那里它们诱导大脑胰岛素抵抗、炎症和细胞死亡（外在途径）。这些异常建立或有助于传播与 ER 应激和神经酰胺生成增加相关的神经退行性变级联反应，从而加剧大脑胰岛素抵抗、细胞死亡、髓鞘变性和神经炎症。这些数据表明，应该针对由有毒神经酰胺、ER 应激和胰岛素抵抗介导的信号转导异常网络，以破坏驱动 AD 神经退行性变级联反应的正反馈回路。
