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.
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