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MISSENSE MUTATIONS IN INSULIN - DEGRADING ENZYME ASSOCIATED WITH A DIABETIC PHENOTYPE IN RATS DECREASE Abeta DEGRADATION IN BRAIN



MISSENSE MUTATIONS IN INSULIN - DEGRADING ENZYME ASSOCIATED WITH A DIABETIC PHENOTYPE IN RATS DECREASE Abeta DEGRADATION IN BRAIN



Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 19 8



Abeta levels in AD are determined by both anabolism and catabolism, however little is known about the latter. We previously identified insulin-degrading enzyme (IDE) as the principal protease that degrades Abeta in cell cultures. The membrane protease neprilysin (NEP) has also been implicated in Abeta catabolism, but the relative roles of IDE and NEP are undefined. Genetic studies of FAD show linkage near the IDE gene. To examine whether naturally occurring SNPs in IDE can affect an organism's ability to degrade Abeta and to determine the relative roles of IDE and NEP in Abeta degradation, we utilized the diabetic GK rat, which has a defect in IDE-mediated catabolism of insulin due to two missense mutations (Fakharai-Rad et al., Hum Mol Genet, 2000). We compared 125I-Abeta1-40 degradation by primary fibroblast cultures, brain soluble fractions and brain membranes of 4 GK and 5 control Wistar rats in the presence of various protease inhibitors. We confirmed that the amino acid-altering SNPs were present in our GK rats and absent in controls, and that IDE protein expression was equal in both groups. GK rat primary fibroblast cultures had 24% less degradation of Abeta in 3 hours (p=0.007), and 125I-insulin degradation was similarly decreased. GK brain membranes had 32% less Abeta degradation at 8 hrs (p=0.0004). >90% of Abeta degradation by the fibroblasts and apprx80% by the brain membranes was inhibited by insulin, a competitive inhibitor of IDE. Thiorphan, an inhibitor of NEP, prevented apprx15% of brain membrane Abeta degradation. Thus, IDE appears to be the major Abeta-degrading enzyme in brain membranes. Moreover, naturally occurring mutations in IDE can decrease Abeta degradation in brain.

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