The metabolic syndrome (MetS) and Alzheimer's disease share several pathological features, including insulin resistance, abnormal protein processing, mitochondrial dysfunction and elevated inflammation and oxidative stress. The MetS constitutes elevated fasting glucose, obesity, dyslipidaemia and hypertension and increases the risk of developing Alzheimer's disease, but the precise mechanism remains elusive. Insulin resistance, which develops from a diet rich in sugars and saturated fatty acids, such as palmitate, is shared by the MetS and Alzheimer's disease. Extracellular vesicles (EVs) are also a point of convergence, with altered dynamics in both the MetS and Alzheimer's disease. However, the role of palmitate- and glucose-induced insulin resistance in the brain and its potential link through EVs to Alzheimer's disease is unknown. We demonstrate that palmitate and high glucose induce insulin resistance and amyloid precursor protein phosphorylation in primary rat embryonic cortical neurons and human cortical stem cells. Palmitate also triggers insulin resistance in oligodendrocytes, the supportive glia of the brain. Palmitate and glucose enhance amyloid precursor protein secretion from cortical neurons via EVs, which induce tau phosphorylation when added to naïve neurons. Additionally, EVs from palmitate-treated oligodendrocytes enhance insulin resistance in recipient neurons. Overall, our findings suggest a novel theory underlying the increased risk of Alzheimer's disease in MetS mediated by EVs, which spread Alzheimer's pathology and insulin resistance.

中文翻译：

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棕榈酸和葡萄糖增加细胞外囊泡中的淀粉样前体蛋白：代谢综合征和阿尔茨海默病之间缺失的联系

代谢综合征（MetS）和阿尔茨海默病有一些共同的病理特征，包括胰岛素抵抗、蛋白质加工异常、线粒体功能障碍以及炎症和氧化应激升高。MetS 会导致空腹血糖升高、肥胖、血脂异常和高血压，并增加患阿尔茨海默病的风险，但其确切机制仍不清楚。胰岛素抵抗是由于富含糖和饱和脂肪酸（例如棕榈酸酯）的饮食而产生的，代谢综合征和阿尔茨海默氏病都有这种现象。细胞外囊泡 (EV) 也是一个交汇点，在 MetS 和阿尔茨海默氏病中都具有变化的动力学。然而，棕榈酸和葡萄糖诱导的胰岛素抵抗在大脑中的作用及其通过 EV 与阿尔茨海默病的潜在联系尚不清楚。我们证明，棕榈酸和高葡萄糖会诱导原代大鼠胚胎皮质神经元和人皮质干细胞的胰岛素抵抗和淀粉样蛋白前体蛋白磷酸化。棕榈酸还会引发少突胶质细胞（大脑的支持性神经胶质细胞）的胰岛素抵抗。棕榈酸和葡萄糖通过 EV 增强皮质神经元的淀粉样前体蛋白分泌，当添加到幼稚神经元时，EV 会诱导 tau 磷酸化。此外，来自棕榈酸酯处理的少突胶质细胞的 EV 增强了受体神经元的胰岛素抵抗。总体而言，我们的研究结果提出了一种新的理论，即 EV 介导的 MetS 中阿尔茨海默病风险增加，而 EV 会传播阿尔茨海默病病理和胰岛素抵抗。