Abstract

Epigallocatechin-3-gallate (EGCG), a catechin found in green tea, has been previously investigated for its neuroprotective effects in vitro and in vivo. In the present study, we aimed to evaluate its possible beneficial effects in a well-established preclinical mixed model of familial Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) based on the use of transgenic APPswe/PS1dE9 (APP/PS1) mice fed with a high fat diet (HFD). C57BL/6 wild-type (WT) and APP/PS1 mice were used in this study. APP/PS1 mice were fed with a palmitic acid–enriched HFD (APP/PS1 HFD) containing 45% of fat mainly from hydrogenated coconut oil. Intraperitoneal glucose tolerance tests (IP-GTT) and insulin tolerance tests (IP-ITT) were performed. Western blot analyses were performed to analyse protein expression, and water maze and novel object recognition test were done to evaluate the cognitive process. EGCG treatment improves peripheral parameters such as insulin sensitivity or liver insulin pathway signalling, as well as central memory deficits. It also markedly increased synaptic markers and cAMP response element binding (CREB) phosphorylation rates, as a consequence of a decrease in the unfolded protein response (UPR) activation through the reduction in the activation factor 4 (ATF4) levels and posterior downregulation of protein tyrosine phosphatase 1B (PTP1B). Moreover, EGCG significantly decreased brain amyloid β (Aβ) production and plaque burden by increasing the levels of α-secretase (ADAM10). Also, it led to a reduction in neuroinflammation, as suggested by the decrease in astrocyte reactivity and toll-like receptor 4 (TLR4) levels. Collectively, evidence suggests that chronic EGCG prevents distinct neuropathological AD-related hallmarks. This study also provides novel insights into the metabolic and neurobiological mechanisms of EGCG against cognitive loss through its effects on UPR function, suggesting that this compound may be a promising disease-modifying treatment for neurodegenerative diseases.

中文翻译：

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Epigallocatechin-3-Gallate（EGCG）通过调节APPswe / PS1dE9小鼠中未折叠的蛋白质应答，改善了由致肥胖饮食引起的认知障碍

摘要

Epigallocatechin-3-gallate（EGCG）是一种在绿茶中发现的儿茶素，先前已对其在体外和体内的神经保护作用进行了研究。在本研究中，我们旨在评估基于转基因APPswe / PS1dE9（APP / PS1）的成熟的家族性阿尔茨海默氏病（AD）和2型糖尿病（T2DM）临床前混合模型的可能有益作用高脂饮食（HFD）喂养的小鼠。C57BL / 6野生型（WT）和APP / PS1小鼠用于这项研究。给APP / PS1小鼠饲喂富含棕榈酸的HFD（APP / PS1 HFD），该脂肪含有45％的脂肪，这些脂肪主要来自氢化椰子油。进行了腹腔内葡萄糖耐量测试（IP-GTT）和胰岛素耐量测试（IP-ITT）。进行蛋白质印迹分析以分析蛋白质表达，并进行水迷宫和新型物体识别测试以评估认知过程。EGCG治疗改善了外周参数，例如胰岛素敏感性或肝胰岛素途径信号传导，以及中枢记忆缺陷。它还显着增加了突触标记和cAMP反应元件结合（CREB）的磷酸化率，通过降低活化因子4（ATF4）水平和蛋白质酪氨酸磷酸酶1B（PTP1B）的后向下调来降低未折叠的蛋白质应答（UPR）活化的结果。此外，EGCG通过增加α-分泌酶（ADAM10）的水平显着降低了脑淀粉样蛋白（Aβ）的产生和斑块负担。同样，它也导致神经炎症的减少，如星形胶质细胞反应性和toll样受体4（TLR4）水平降低所表明的。总的来说，证据表明，慢性EGCG可以预防与神经病理学AD相关的明显特征。这项研究还通过其对UPR功能的影响，为EGCG对抗认知丧失的代谢和神经生物学机制提供了新颖的见解，