Two substrates of insulin-degrading enzyme (IDE), amyloid ␤-protein (A␤) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of A␤ levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases A␤ and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE ؊͞؊). IDE deficiency resulted in a >50% decrease in A␤ degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE ؊͞؊ mice showed increased cerebral accumulation of endogenous A␤, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the ␤-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD. I nsulin-degrading enzyme (IDE, insulysin) is an Ϸ110-kDa thiol zinc-metalloendopeptidase located in cytosol, peroxisomes, endosomes, and on the cell surface (1-4) that cleaves small proteins of diverse sequence, many of which share a propensity to form ␤-pleated sheet-rich amyloid fibrils under certain conditions [e.g., amyloid ␤-protein (A␤), insulin, glucagon, amylin, atrial natriuretic factor, and calcitonin] (5, 6). IDE is the major enzyme responsible for insulin degradation in vitro (1), but the extent to which it mediates insulin catabolism in vivo has been controversial, with doubts expressed that IDE has any physiological role in insulin catabolism (7). Insulin, which is critical for glucose, lipid, and protein metabolism, as well as for cell growth and differentiation, is cleared mainly by the liver and kidney, but most other tissues also degrade the hormone. It was recently shown that transferring an Ϸ3.7-cM chromosomal region containing the IDE gene from an inbred rat model of type 2 diabetes mellitus (DM2) (the GK rat) to a normoglycemic rat recapitulated several features of the diabetic phenotype, including hyperinsulinemia and postprandial hyperglycemia (8). The GK allele of IDE in this chromosomal region was found to bear two missense mutations that, when transfected into COS-1 cells, resulted in 31% less insulin degradation compared with cells transfected with the WT allele. Furthermore, the IDE region of chromosome 10q has been genetically linked to DM2 (9, 10) and to elevated fasting glucose levels [20-year means (1...

Converging evidence suggests that the accumulation of cerebral amyloid beta-protein (Abeta) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Abeta thus represents a novel therapeutic approach to lowering steady-state Abeta levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Abeta levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Abeta-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo.