The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration.
The role of ATP-binding cassette transporter A1 in Alzheimer's disease and neurodegeneration.
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DOI：
10.1016/j.bbalip.2010.02.010
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Lefterov I
中科院分区：
文献类型：
--
作者：
Koldamova R;Fitz NF;Lefterov I
atp结合盒转运蛋白A1 - ABCA1是人类病理中研究最广泛的转运蛋白。在发现ABCA1基因位点的突变导致严重的家族性高密度脂蛋白（HDL）缺乏和纯合子形式的丹吉尔病之后，ABCA1立即成为许多学术和制药实验室的主要研究对象。该蛋白是细胞内胆固醇外排的主要调节因子，这是新生HDL颗粒生物发生和形成的初始和必要步骤。核肝X受体（LXR）对ABCA1的转录调控为药物发现和开发用于治疗动脉硬化的合成LXR配体/ABCA1激活剂提供了起点。一系列报道揭示了ABCA1在Aβ沉积和清除中的作用，以及一些ABCA1遗传变异与阿尔茨海默病（AD）风险之间的关联，为ABCA1的研究带来了新的维度。LXR-ABCA1-APOE调控轴现在被认为是AD的一个有希望的治疗靶点，其中包括唯一被证实的AD -APOE的危险因素，在两个不同的水平上- LXR的转录调控和ABCA1控制的脂化，后者可以影响a β聚集和淀粉样蛋白清除。本文将对ABCA1的研究成果进行综述，特别是与阿尔茨海默病和神经退行性变的关系。
ATP-binding cassette transporter A1 — ABCA1, is the most extensively studied transporter in human pathology. ABCA1 became a primary subject of research in many academic and pharmaceutical laboratories immediately after the discovery that mutations at the gene locus cause severe familial High Density Lipoprotein (HDL) deficiency and, in the homozygous form — Tangier disease. The protein is the major regulator of intracellular cholesterol efflux which is the initial and essential step in the biogenesis and formation of nascent HDL particles. The transcriptional regulation of ABCA1 by nuclear Liver X Receptors (LXR) provided a starting point for drug discovery and development of synthetic LXR ligands/ABCA1 activators for treatment of arteriosclerosis. A series of reports that revealed the role of ABCA1 in Aβ deposition and clearance, as well as the possibility for association of some ABCA1 genetic variants with risk for Alzheimer’s disease (AD) brought a new dimension to ABCA1 research. The LXR-ABCA1-APOE regulatory axis is now considered a promising therapeutic target in AD, which includes the only proven risk factor for AD – APOE, at two distinct levels – transcriptional regulation by LXR, and ABCA1 controlled lipidation which can influence Aβ aggregation and amyloid clearance. This review will summarize the results of research on ABCA1, particularly related to AD and neurodegeneration.
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