虾青素通过调节PPARγ信号通路抑制阿尔茨海默病转基因小鼠脑内Aβ形成的分子机制

Alzheimer’s disease (AD) is a neurodegenrative disorder characterized with β-amyloid protein (Aβ) deposition and plaque formation in the brain. Aβ is generated from β-amyloid precursor protein (APP) via a proteolytic process of β- and γ-secretases. Recent studies have shown that as an antioxidant, astaxanthin (ATX) can protect neurons from Aβ injury. Protective mechanism of ATX in AD is primarily through antioxidant effects, anti-inflammatory effects and anti-apoptotic effects. Furthermore, ATX can through the brain blood barrier into the brain. However, the effect and the underlying mechanism of whether ATX is able to inhibit Aβ deposition in AD brain has not been evaluated. Therefore, we raise the hypothesis that (1) ATX prevents APP amyloid metabolic pathway by PPARγ activation, resulting in inhibition of BACE1 activity and APH1 expression, decreasing Aβ production and reducing Aβ secretion to extracellular. (2) ATX can improve mitochondrial MMP, ATP and mitochondrial respiratory activity complex, reduce ROS to restore mitochondrial function and maintain the integrity of mitochondria, reducing nerve cell apoptotic death by activating PPARγ. The project intends to use APP / PS1 transgenic mice and transfection APPsw in SH-SY5Y cell line as a model, investigates the expression of AD-related protein (APP, Aβ and α-, β-, γ- secretase) and mitochondrial function of the ATX by adjusting the PPARγ signaling pathway, obtains reliable evidence of ATX suppressing Aβ generation and deposition. This project will helpful to explore the mechanisms by which ATX modulates the activity of Aβ generation related secretases, and provide a clue for potential use of ATX for the prevention and therapy of AD.

阿尔茨海默病(AD)的主要病理特征之一是脑内β-淀粉样蛋白(Aβ)沉积形成的老年斑。虾青素(ATX)是一种可通过血脑屏障入脑的抗氧化剂，体外研究表明ATX对Aβ引起的神经元损伤具有保护作用。我们的前期工作证实ATX可以抑制APP/PS1转基因小鼠脑内Aβ沉积和β-、γ-分泌酶的表达，减少APPsw转染细胞的Aβ分泌，但ATX抑制Aβ产生和沉积的机制尚不清楚。本项目拟采用转基因小鼠及APPsw转染细胞为体内外模型，对ATX通过调节PPARγ信号通路影响AD相关蛋白(APP、Aβ和α-、β-、γ-分泌酶)等的表达与线粒体功能进行系列研究，获取ATX抑制Aβ产生与沉积的可靠证据，阐明ATX通过PPARγ调节线粒体功能参与Aβ产生和淀粉样蛋白老年斑沉积的分子机制，为将ATX用于AD防治提供充分的理论依据。

阿尔茨海默病 (AD) 的主要病理特征之一是脑内β-淀粉样蛋白 (Aβ) 沉积形成的老年斑。虾青素 (ATX) 是一种可穿越血脑屏障进入脑组织的抗氧化剂，体外研究表明ATX对Aβ引起的神经元损伤具有保护作用。本项目采用APP/PS1转基因小鼠及APPsw转染细胞为体内外模型，探讨ATX影响AD相关蛋白 (APP、Aβ和α-、β-、γ-分泌酶) 等的表达与线粒体功能的相关机制，同时，项目组也探讨了一种新型的噻唑烷二酮类化合物GQ -16，研究表明噻唑烷二酮类药物能改善AD患者认知功能，也是PPARγ的激动剂，同时PPARγ的激活可以抑制β-分泌酶（BACE1）的表达并抑制Aβ生成，项目组证明GQ -16通过激活PPARγ来抑制APP剪切的淀粉样蛋白产生途径，从而减少Aβ的产生和沉积和改善线粒体功能，保护神经细胞的机制。.研究结果表明ATX主要通过PPARα调节Akt/GSK3β/β-catenin信号通路以及改善线粒体相关呼吸功能来抑制Aβ产生与沉积，从而抑制细胞凋亡，促进细胞存活；同时GQ-16可能通过PPARγ激活Akt/GSK3β/β-catenin和PKA/ERK/CREB信号通路，抑制Nf-κB信号通路来抑制APP剪切的淀粉样蛋白产生途径，从而减少Aβ的产生和沉积；同时GQ-16还能够改善线粒体的功能，从而达到保护细胞，抑制神经细胞凋亡性死亡。以上研究结果进一步揭示ATX和GQ-16参与AD发生发展的机理，为将ATX和GQ-16用于AD防治的新策略提供充分的理论依据。.本项目已发表SCI收录期刊论文4篇，中文论文1篇，会议论文3篇，参与申请1项专利，培养了2名硕士研究生，为项目组将来以抑制致病蛋白沉积的药物及化合物筛选与研发奠定基础。

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