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The effects of peripheral hypercholesterolemia on brain cholesterol metabolism.

机译：外周血胆固醇过多对脑胆固醇代谢的影响。

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摘要

Disrupted cholesterol homeostasis in the brain and the peripheral circulation is associated with the etiology of Alzheimer's disease (AD). Since the brain's cholesterol metabolism is segregated, attenuated cholesterol metabolism in the AD brain is unlikely to be a direct consequence of elevated plasma cholesterol. Thus, we hypothesized that there should be signals derived from the peripheral circulation secondary to the chronic hypercholesterolemia that compromises normal brain metabolism.;We induced hypercholesterolemic condition in young, middle-aged, and old male Brown Norway rats by feeding cholesterol+cholic acid supplemented purified diet (CCA) for either short-term (1 month) or long-term (3-4 month).;The CCA created a "humanized" diet-induced hypercholesterolemia (DIH) in the peripheral compartment by significantly increasing total cholesterol in plasma and liver and shifting lipoprotein peaks from HDL to VLDL, while the brain's lipid profile was solely age-dependent. ELISA on the rat brain extracts showed that pathogenic Abeta42 increased whereas neuroprotective Abeta40 decreased with advancing age, and AD pathogenic factor Abeta42/40 ratio tended to be increased by DIH. Morris water maze test revealed age-related spatial learning decline, and the age effects were somewhat accelerated by DIH. Hippocampus microarray analysis revealed that the prolonged DIH in old rats was associated with >2-fold change in expression of >2000 probe sets.;These data suggest that the development of AD-like pathologies was age-dependent and it was accelerated by DIH. The DIH effects implicate the presence of the brain-body communication which mediates peripheral changes associated with DIH to the brain, thereby aggravating AD-like pathologies.
机译：脑部和外周循环中胆固醇稳态的破坏与阿尔茨海默氏病（AD）的病因有关。由于大脑的胆固醇代谢是隔离的，因此AD大脑中胆固醇代谢的减弱不太可能是血浆胆固醇升高的直接结果。因此，我们假设应该从慢性高胆固醇血症继发于周围循环的信号中损害正常的脑代谢。;我们通过补充胆固醇和胆酸补充了幼年，中年和老年雄性褐挪威大鼠的高胆固醇血症。短期（1个月）或长期（3-4个月）的纯净饮食（CCA）。CCA通过显着增加体内总胆固醇，在外周区隔中创建了“人源化”饮食诱发的高胆固醇血症（DIH）。血浆和肝脏以及脂蛋白峰从HDL转变为VLDL，而大脑的脂质分布则仅取决于年龄。大鼠脑提取物的ELISA结果显示，随着年龄的增长，致病性Abeta42升高，而神经保护性Abeta40降低，而DIH会增加AD致病因子Abeta42 / 40的比例。莫里斯水迷宫测试揭示了与年龄相关的空间学习能力下降，而DIH对年龄的影响有所加快。海马微阵列分析显示，老龄大鼠的DIH延长与> 2000个探针集的表达变化> 2倍有关。这些数据表明，AD样病理的发展是年龄依赖性的，并被DIH加速。 DIH效应暗示了介导与DIH相关的周围环境变化的大脑与身体的交流，从而加剧了AD样疾病。

著录项

  • 作者

    Yamada, Naomi.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Health Sciences Nutrition.;Gerontology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 176 p.
  • 总页数 176
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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