Extending in-vitro evidence that insulin-degrading enzyme (IDE) may be involved in the clearance of the Aβ peptide, a report in the 12 March issue of PNAS finds that IDE knockout mice have higher cerebral accumulation of both Aβ and the AβPP intracellular domain.

An association between AD, hyperinsulinemia, and diabetes has been posited in recent research reports. Epidemiologic studies have linked both type 2 (adult-onset) diabetes mellitus and hyperinsulinemia to an increased risk of AD. Furthermore, there are hints that IDE genotype can affect the risk of developing late-onset Alzheimer's disease (see ARF related news story) and ARF meeting report).

In the present study, researchers at Harvard University and the Mayo Clinic in Jacksonville, Florida, used IDE knockout mice to look at the effects of IDE deficiency on markers of both diabetes and AD. In their first experiment, first author Wesley Farris, with Suzanne Guenette and colleagues, showed that brain homogenates, as well as intact, living neurons from mice lacking IDE, degraded less synthetic Aβ1-40 than did tissue or neurons from IDE wild-type mice. Similar deficits were found in the insulin degradation capacity of the liver of IDE knockout mice.

The researchers then asked whether this meant that IDE knockout mice have higher levels of endogenous Aβ As measured by ELISA, 12-week-old IDE-deficient mice had a 64 percent elevation of cerebral Aβ1-40 compared to wild-type. At six months, IDE-deficient mice had significant elevations of both Aβ1-40 and 1-42, though the Aβ1-40 elevation relative to wild-type had dropped from the 12-week levels.

IDE has also been found to degrade the intracellular domain (AICD) that Aß leaves behind after AβPP is cleaved. AICD has been shown to be transcriptionally active (see ARF related news story), perhaps with a role in apoptosis (see ARF related news story). Farris and colleagues found that levels of AICD were also elevated in brains of IDE knockout mice. Finally, the researchers report that the IDE-deficient mice showed two hallmarks of type 2 diabetes: hyperinsulinemia and glucose intolerance.

In their discussion, the authors offer two hypotheses on apparent links among type 2 diabetes, hyperinsulinemia, and AD. "A primary decrease in IDE function can put an individual at risk for these conditions, as suggested by the genetic evidence for an AD and a DM2 gene in the same IDE-containing region of chromosome 10q. Chronic hyperinsulinemia, whether caused by IDE dysfunction or another mechanism, could provide an avid competitive substrate to IDE, resulting in decreased degradation and resultant gradual accumulation of Aβ" the authors write.—Hakon Heimer


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News Citations

  1. Insulin-Degrading Enzyme Not, After All, a Risk Factor for AD?
  2. Stockholm: Degradation on the Rise
  3. Aβ's Shadowy Sibling—What Becomes of the Intracellular Domain?

Further Reading

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Primary Papers

  1. . Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7. PubMed.