Curcumin通过HO-1/PPARγ调控ABCA1跨膜胆固醇转运在AD中发挥脑保护作用的分子机制

Cholesterol transmembrane transport deficits in neurons are closely correlated with the pathogenesis of Alzheimer's disease (AD), and ABCA1 transmembrane transport regulated by LXRβ/RXRα play a key role during the process, which is a new therapeutic target for treatment of AD. Our previous study found that curcumin significantly increased the expression of HO-1 and PPARγ, enhanced the expression of ABCA1, and increased cholesterol efflux of the neurons in AD. Based on the recent findings that HO-1 could activate LXRβ, and PPARγ was closely related to LXRβ/RXRα, we propose "the molecular mechanisms of neuroprotective effects of curcumin on ABCA1 transmembrane-transport pathway via activating HO-1/PPARγ". In this study, N2ABP1 cells stably expressing APP695sw, AD transgenic mice and the primary hippocampal neurons from the mice will be used; the effects of curcumin on the cholesterol efflux from neurons and its neuroprotective effects will be firstly investigated. Then, whether the effects of curcumin are depended on the activation of the upsteam target molecules（HO-1/PPARγ）and downstream target molecules（ABCA1 transmembrane-transport system）of LXRβ/RXR will be investigated, respectively. Our study will explore the molecular mechanism of neuroprotective effects of curcumin from a new sight and further elucidate the multiple protective mechanisms of curcumin on prevention and treatment of AD.

神经元跨膜胆固醇转运障碍与阿尔茨海默病（AD）的发病密切相关,且LXRβ/RXRα调控的ABCA1跨膜胆固醇转运起关键作用,是AD治疗新靶点。我们研究证实Curcumin诱导HO-1和PPARγ表达,并增强ABCA1表达,促进神经元胆固醇外流。因HO-1可激活LXRβ且PPARγ与LXRβ/RXRα密切相关,本项目提出：Curcumin通过HO-1/PPARr激活LXRβ/RXRα调控ABCA1跨膜胆固醇转运发挥脑保护作用。本研究选用离体AD模型（N2ABP1细胞和转基因鼠海马原代神经元）及AD转基因鼠,先观察Curcumin对神经元排出胆固醇的影响及脑保护的效应,再分析该作用是否依赖于LXRβ/RXRα的上游HO-1/PPARγ及下游ABCA1跨膜胆固醇转运体系。本课题从一个全新的视角探讨Curcumin在AD中发挥脑保护作用的分子机制,进一步阐明Curcumin防治AD的多重保护机制。

神经元跨膜胆固醇转运障碍与阿尔茨海默病（AD）的发病密切相关,且LXRβ/RXRα调控的ABCA1跨膜胆固醇转运起关键作用,是AD 治疗新靶点。我们研究证实Curcumin 诱导HO-1 和PPARγ表达,并增强ABCA1 表达,促进神经元胆固醇外流。我们选用离体AD 模型（N2ABP1 细胞）及AD 转基因鼠,先观察Curcumin 对神经元排出胆固醇的影响及脑保护的效应,再分析该作用是否依赖于LXRβ/RXRα的上游HO-1/PPARγ及下游ABCA1 跨膜胆固醇转运体系。研究表明：Curcumin 通过HO-1/PPARr 激活LXRβ/RXRα调控ABCA1 跨膜胆固醇转运，在AD中发挥了脑保护作用。本课题为找到AD治疗的新途径提供重要实验依据。