Transgenic h-APP mice models of Alzheimer's disease indicate that the production of the Abeta 1-42 peptide, or its polymerization into amyloid filaments, or both, are part of the pathogenic pathway leading to Alzheimer's disease. In the parent grant to this Supplemental Application, we proposed to determine whether two inflammatory proteins, apolipoprotein E and antichymotrypsin, played a role in amyloid formation in APP transgenic mice, as previous in vitro and epidermiological evidence had predicted. We also proposed to introduce peptide blockers of the ACT-ABeta and apo E-ABeta interactions into the transgenic mice and to determine if they prevent apoE- and ACT-dependent amyloid formation. Recent results have clearly demonstrated that ACT is an amyloid promoter in vivo and have confirmed earlier work showing that, in mice, no filamentous amyloid forms in the absence of apoE (mice lack ACT already). The conclusion is that ABeta cannot form Alzheimer amyloid in mice without help from a """"""""pathological chaperone"""""""". The critical question that remains is whether amyloid formation causes the cognitive and memory deficits associated with Alzheimer's disease or whether it is merely a marker of the increased production of ABeta 1-42 induced, for example, by APP mutations. Unfortunately, it has not been easy to measure age- and amyloid associated memory decline in the transgenic APP mice. This problem has recently been solved by the Co-PI of this Supplement, Dr. Gary Arendash, through the use of a new test, the Radial Arm Water Maze (RAWM). The test has successfully correlated working memory deficits with amyloid formation in Tg2576 and Tg2576-PS1 mice and shown that ABeta vaccination prevents the development of memory loss. In preliminary results presented here, aged PD-APP mice were also found to develop memory loss detected by the RAWM. More important, we have found that apoE is essential for both the amyloid formation and the cognitive decline. We now propose to solidify and extend this result by a thorough behavioral analysis of the transgenic mice that are the subject of the parent grant. If the preliminary results are confirmed, we are likely to discover that it is either the process or product of ABeta polymerization that is neurotoxic and leads to cognitive decline in mice and that Abeta 1-42 and diffuse amyloid is by itself fairly harmless. Such a conclusion will be important for the design of Alzheimer therapies. ? ?
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