Triangulated mal-signaling in Alzheimer's disease: roles of neurotoxic ceramides, ER stress, and insulin resistance reviewed.
Triangulated mal-signaling in Alzheimer's disease: roles of neurotoxic ceramides, ER stress, and insulin resistance reviewed.
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DOI：
10.3233/jad-2012-111727
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发表时间：
2012
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影响因子：
--
通讯作者：
de la Monte SM
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作者：
de la Monte SM
神经酰胺是由胰岛素抵抗、炎症和内质网应激介导的细胞毒性和细胞死亡的脂质信号分子。然而，胰岛素抵抗会扰乱脂代谢，从而促进神经酰胺的积累，并伴随着炎症和内质网应激。在这里，我们讨论了两条主要的途径，外部的和内在的，在通过三角化的异常信号网络传播AD类型的神经退变时，这两条途径汇聚并经常重叠。首先，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全身性胰岛素抵抗疾病促进神经退行性变的证据。从机制上讲，我们认为，在中枢神经系统外组织(如肝脏)中产生的有毒神经酰胺被释放到外周血液中，然后通过血脑屏障进入大脑，在那里它们诱导脑胰岛素抵抗、炎症和细胞死亡(外部途径)。然后，我们讨论了内源性或原发性脑内胰岛素/胰岛素样生长因子抵抗所介导的神经退行性变的内在途径的作用，它损害了神经元和少突胶质细胞的存活、能量代谢、膜完整性、细胞骨架功能和AβPP-Aβ的分泌。最终结果是内质网应激和神经酰胺生成增加，这会加剧大脑胰岛素抵抗、细胞死亡、髓鞘变性和神经炎症。总之，这些数据表明，由毒性神经酰胺、内质网应激和胰岛素抵抗介导的三角异常信号网络应该被靶向破坏驱动AD神经退行性变级联的正反馈环路。
Ceramides are lipid signaling molecules that cause cytotoxicity and cell death mediated by insulin resistance, inflammation, and endoplasmic reticulum (ER) stress. However, insulin resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and ER stress. Herein, we discuss two major pathways, extrinsic and intrinsic, that converge and often overlap in propagating AD-type neurodegeneration via a triangulated mal-signaling network. First, we review evidence that systemic insulin resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. 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). Then we discuss the role of the intrinsic pathway of neurodegeneration which is mediated by endogenous or primary brain insulin/IGF resistance, and impairs neuronal and oligodendrocyte survival, energy metabolism, membrane integrity, cytoskeletal function, and AβPP-Aβ secretion. The end result is increased ER stress and ceramide generation, which exacerbate brain insulin resistance, cell death, myelin degeneration, and neuroinflammation. Altogether, the data suggest that the triangulated 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.