Core--Amyloid Beta Analysis

核心--淀粉样蛋白β分析

• 批准号: 6324572
• 负责人: STEVEN YOUNKIN
• 金额: $ 22.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6324572
• 关键词: aging; amyloid proteins; biomedical facility; brain metabolism; gene targeting; genetically modified animals; laboratory mouse

Studies that we have performed in the past several years shown that a fundamental effect of aging, DS, and the FAD-linked betaAPP, PS1 and PS2 mutations is to increase the extracellular concentration of Abeta. The betaAPP717, PS1 and PS2 mutations selectively increase Abeta42(43). The betaAPPdeltaNL mutation, DS, and aging increase both Abeta40 and Abeta42(43). These influences are clearly operative in humans in vivo because they are demonstrable in plasma. Increase extracellular Abeta42(43), which is invariably observed in the AD brain, so these results provide strong evidence that Abeta deposition or tightly associated changes in Abeta metabolism may cause the complex pathologic cascade that produces AD. The Abeta analysis core will provide measurements of Abeta that enable the specific projects to evaluate factors that influence Abeta dn to evaluate the role of Abeta and to evaluate the role of Abeta in pathological, electrophysiological, neurochemical, and behavioral changes that occur in the Tg2576 transgenic model of AD. Samples will be prepared and analyzed so that Abeta1-40, Abeta1-42(43) and other forms of Abeta can be assessed not only in the insoluble fraction. This core will also generate control transgenic mice like Tg2576 except that wild type betaAPP695 is expressed. The betaAPPP670N/671L transgene expressed in Tg2576 produces 5-6 times more Abeta that wild type betaAPP. Thus, these mice will serve as an important control to determine whether increased Abeta production is responsible for the age-dependent pathological, electrophysiological, neurochemical, and behavioral changes that occur in Tg2576 mice.

我们在过去几年中进行的研究表明，衰老、DS和FAD相关的betaAPP、PS1和PS2突变的基本效应是增加Abeta的细胞外浓度。 β APP 717、PS1和PS2突变选择性地增加A β 42（43）。 betaAPPdeltaNL突变、DS和衰老增加了A β 40和A β 42（43）。 这些影响在人体体内明显有效，因为它们在血浆中可证实。 增加细胞外A β 42（43），这是在AD大脑中始终观察到的，因此这些结果提供了强有力的证据，表明A β沉积或A β代谢中密切相关的变化可能导致产生AD的复杂病理级联反应。 Abeta分析核心将提供Abeta的测量，使特定项目能够评估影响Abeta dn的因素，以评估Abeta的作用，并评估Abeta在AD的Tg 2576转基因模型中发生的病理学，电生理学，神经化学和行为变化中的作用。 将制备和分析样品，以便不仅可以在不溶性部分中评估A β 1 -40、A β 1 -42（43）和其他形式的A β。 该核心也将产生对照转基因小鼠，如Tg 2576，除了表达野生型β APP 695。 在Tg 2576中表达的β APP 670 N/671 L转基因产生的Abeta是野生型β APP的5-6倍。 因此，这些小鼠将作为一个重要的对照，以确定是否增加的Abeta生产是负责的年龄依赖性病理，电生理，神经化学，和行为的变化，发生在Tg 2576小鼠。