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PLoS ONE:胆固醇诱发老年痴呆症和心脏病的作用机制

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时间:2013-04-19 15:33 点击:
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 众所周知,血液中胆固醇水平过高会增加患老年痴呆症和心脏病的风险,但人们对这背后的机制却知之甚少.

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来自国际一个研究小组的研究人员通过对两个非常罕见的疾病—唐氏综合症和尼曼匹C型病的研究发现:胆固醇能破坏细胞的正常分裂程序,导致其分裂紊乱,从而使其产生有缺陷的子细胞.这项新的研究已于本周发表在PLoS ONE期刊上.

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Antoneta Granic和 Huntington Potter博士称:胆固醇(特别是低密度脂蛋白,也称为“坏胆固醇”)能使人和小鼠的细胞分裂紊乱,迫使正常细胞将已经复制的染色体不均等地分配到下一 代.结果导致子细胞中染色体数目有的增加有的减少,细胞内基因的数目也有的增加有的减少,随着细胞分裂的进行,这些有缺陷的子细胞越积越多.而正常情况 下,染色体复制以后是平均分配到两个子细胞中去的.

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Granic和Potter重点研究了那些携带了3份染色体(人的21号染色体和小鼠的16号染色体)的子细胞,这些子细胞携带的多余的染色体上有一个编码淀粉样肽的基因,淀粉样肽是具有神经毒性的淀粉样蛋白细丝的关键组成部分,并能在老年痴呆症患者的大脑中积累.

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Granic和Potter及其他一些科学家的早期研究发现,多达10%的老年痴呆症患者的细胞包括大脑中的神经元中含有3条21号染色体,而正常 情况下应为两条.因此,从某些方面来看,老年痴呆症是唐氏综合症的另一种表现形式.此外,基因突变亦可以像胆固醇那样导致染色体不均等分裂,从而表明遗传 性和非遗传性老年痴呆症都是由细胞分裂过程中染色体分配不均引起的.

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这项新的研究还发现,患有尼曼匹克C型疾病的儿童的大脑神经元中的三染色体是由影响胆固醇生理功能的突变引起的.这一结果表明,神经退行性疾病本身可能与染色体不均等分离有关. www.zhichidai.com

寻找胆固醇的作用机制将有助于人们寻找治疗特定疾病的方法,如老年痴呆症,动脉粥样硬化甚至癌症,因为所有这些疾病都与细胞不正常分裂有关. 本文来自 治痴呆网

英文原文:

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Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer’s disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy–in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (A?) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated A?, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis’ first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not A?, showing that LDL works differently than A?, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol’s aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol consumption reduces the risk of developing atherosclerosis or AD. These results suggest a novel, cell cycle mechanism by which aberrant cholesterol homeostasis promotes neurodegeneration and atherosclerosis by disrupting chromosome segregation and potentially other aspects of microtubule physiology.

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