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The Life Cycle of Ab: Production and Degradation
By Dennis J. Selkoe

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Abstract: Although elevated brain levels of Ab occur universally in AD, only a minority of cases involves increased Ab production, primarily those with presenilin mutations. Therefore, defects in proteases that degrade Ab could underlie some cases of familial and sporadic AD. An unbiased screen of cultured cells for Ab-degrading proteases previously revealed IDE as the principal protease that degrades naturally secreted Aß in both neuronal and microglial cultures (Qiu et al, JBC, 1997, 1998). We have now assayed Ab-degrading capacity in total homogenates and membrane fractions of normal and AD brains. The degree of Ab degradation correlated inversely the levels of soluble but not insoluble Ab in the tissue. Insulin, the most avid substrate of IDE, inhibited Ab-degrading activity ~70% in the membrane fraction of human brain, whereas thiorphan and phosphoramidon, inhibitors of neprilysin, blocked ~25%. In mouse brain membrane fractions, Ab degradation was similarly inhibited ~70% by insulin and ~30% by thiorphan. Subcellular fractionation of IDE-transfected cells revealed that membrane-associated IDE lowered the levels of endogenous intracellular Ab in the vesicles that generate the peptide. Thus, accruing evidence that IDE can degrade Ab in neural and microglial cultures and in human brain recommended it as a candidate FAD gene. A collaborative study provided evidence of linkage of markers flanking the IDE gene on chromosome 10q to AD in the NIMH families (Bertram et al, Science, 2000). 125I-Ab40 degradation in whole lymphoblast cultures from a subset of the linked families and unrelated controls is now being quantified. We conclude that IDE plays a role in Ab degradation, both intra- and extracellularly, and that neprilysin also contributes to membrane-associated degradation in human and mouse brain. Further study of IDE will be relevant to Ab regulation in AD, whether or not IDE is ultimately found to be genetically implicated.

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