Core--Amyloid Beta Analysis

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突变的基本作用是增加细胞外的β浓度。betaAPP717、PS1和PS2突变选择性地增加Abeta42（43）。betaAPPdeltaNL突变、DS和衰老都会增加Abeta40和Abeta42（43）。这些影响在人体内显然是有效的，因为它们在血浆中是可以证明的。细胞外Abeta42增加（43），这在AD大脑中不可避免地观察到，因此这些结果提供了强有力的证据，证明Abeta沉积或密切相关的Abeta代谢变化可能导致复杂的病理级联反应，从而产生AD。Abeta分析核心将提供Abeta的测量值，使特定项目能够评估影响Abeta的因素，评估Abeta的作用，以及评估Abeta在Tg2576转基因AD模型中发生的病理、电生理、神经化学和行为变化中的作用。将制备和分析样品，使Abeta1-40， Abeta1-42（43）和其他形式的Abeta不仅可以在不溶性部分中进行评估。除了表达野生型betaAPP695外，该核心也会产生Tg2576等对照转基因小鼠。在Tg2576中表达的betaAPPP670N/671L基因产生的β是野生型betaAPP的5-6倍。因此，这些小鼠将作为重要的对照，以确定β生成的增加是否与Tg2576小鼠发生的年龄依赖性病理、电生理、神经化学和行为变化有关。

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.