Core--Amyloid Beta Analysis

我们在过去几年中进行的研究表明，衰老、DS以及FAD相关的APP、PS1和PS2突变的一个基本影响是增加细胞外Abeta的浓度。APP717、PS1和PS2突变选择性地增加了Abeta42(43)。βAPPdeltaNL突变、DS和年龄增加了Abeta40和Abeta42(43)。这些影响显然在活体人体中起作用，因为它们在血浆中是明显的。增加细胞外Abeta42(43)，这在AD大脑中总是可以观察到的，所以这些结果提供了强有力的证据，表明Abeta沉积或密切相关的Abeta代谢变化可能导致产生AD的复杂病理级联。Abeta分析核心将提供对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。将准备和分析样品，以便不仅可以在不溶性部分中评估Abeta1-40、Abeta1-42(43)和其他形式的Abeta。除了表达野生型BetaAPP695外，该核心还将产生像Tg2576这样的对照转基因小鼠。在Tg2576中表达的β-APPP670N/671L转基因菌株产生的β-β是野生型的5-6倍。因此，这些小鼠将作为一个重要的对照，以确定Abeta产生的增加是否与Tg2576小鼠的年龄相关的病理、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.