Dysfunctional pro-ceramide, ER stress, and insulin/IGF signaling networks with progression of Alzheimer's disease.
Dysfunctional pro-ceramide, ER stress, and insulin/IGF signaling networks with progression of Alzheimer's disease.
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DOI：
10.3233/jad-2012-111728
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Tong M
中科院分区：
文献类型：
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作者：
de la Monte SM;Re E;Longato L;Tong M
在阿尔茨海默病（AD）中，脑胰岛素和胰岛素样生长因子（IGF）抵抗和缺乏开始较早，并且随着疾病的严重程度而恶化。介导AD患者脑胰岛素/IGF抵抗进展的因素尚不清楚。我们假设AD的进展是通过负性的相互作用来介导的，这种相互作用促进了毒性神经酰胺的产生和内质网（ER）应激。其基本原理是胰岛素抵抗失调脂质代谢，促进神经酰胺积累，从而增加炎症和压力。后果包括细胞骨架功能和AβPP-Aβ分泌的破坏。本研究将AD分期与人死后脑组织中神经酰胺原基因的激活、神经酰胺水平和ER应激的分子指标相关联。结果表明，在AD中，脑胰岛素/IGF抵抗与多种前神经酰胺基因的组成性激活、神经酰胺水平增加以及前ER应激途径基因和蛋白表达增加相关。几种前神经酰胺和促凋亡ER应激途径分子的表达随着AD严重程度和脑胰岛素/IGF抵抗而增加。相比之下，ER应激分子，帮助维持相对于未折叠的蛋白质反应的稳态，主要是在AD的中期而不是晚期上调。这些研究结果支持我们的假设，即在AD中，由脑胰岛素/IGF抵抗发起的三角形不良信号网络通过神经酰胺和ER应激稳态的失调传播，这些稳态本身促进胰岛素抵抗。因此，一旦建立，必须使用多管齐下的方法来靶向这种混响回路，以破坏AD神经退行性级联反应。
In Alzheimer’s disease (AD), brain insulin and insulin-like growth factor (IGF) resistance and deficiency begin early, and worsen with severity of disease. The factors mediating progression of brain insulin/IGF resistance in AD are not well understood. We hypothesize that AD progression is mediated via negative cross-talk that promotes toxic ceramide generation and endoplasmic reticulum (ER) stress. The rationale is that insulin resistance dysregulates lipid metabolism and promotes ceramide accumulation, and thereby increases inflammation and stress. Consequences include disruption of cytoskeletal function and AβPP-Aβ secretion. The present study correlates AD stage with activation of pro-ceramide genes, ceramide levels, and molecular indices of ER stress in postmortem human brain tissue. The results demonstrated that in AD, brain insulin/IGF resistance was associated with constitutive activation of multiple pro-ceramidegenes, increased ceramide levels, and increased expression of pro-ER stress pathway genes and proteins. Expression of several pro-ceramide and pro-apoptotic ER stress pathway molecules increased with AD severity and brain insulin/IGF resistance. In contrast, ER stress molecules that help maintain homeostasis with respect to unfolded protein responses were mainly upregulated in the intermediate rather than late stage of AD. These findings support our hypothesis that in AD, a triangulated mal-signaling network initiated by brain insulin/IGF resistance is propagated by the dysregulation of ceramide and ER stress homeostasis, which themselves promote insulin resistance. Therefore, once established, this reverberating loop must be targeted using multi-pronged approaches to disrupt the AD neurodegeneration cascade.