A report in next week's PNAS adds to the growing evidence that insulin-degrading enzyme (IDE), or insulysin, plays a role in the degradation of amyloid-β (Aβ).
For some time now, IDE has been touted as a possible risk factor for late-onset Alzheimer's disease, though conclusive genetic evidence linking the two has yet to be found (see ARF related news story). However, evidence for IDE's involvement in the breakdown of Aβ has grown, most recently in a March 12 PNAS paper by Wes Farris and colleagues showing that mice lacking IDE accumulate higher levels of Aβ than wild-type animals do (see ARF related news story). Now, Bonnie Miller and coworkers at the University of Texas Southwestern Medical School, together with colleagues from the Mayo Clinic, Jacksonville, Florida, and the University of Kentucky, Lexington, report strikingly similar findings, strengthening the case against insulysin. Their report first appeared in the PNAS early online edition on May 5.
Like the earlier paper by Farris et al., Miller and colleagues examined the effect of deleting both copies of the IDE gene in mice. In addition, the authors also raised and monitored mice having one good copy of the gene, which may better model allelic polymorphisms that exist in the human population.
Miller et al. confirmed lack of IDE gene expression by real-time PCR measurements. In brain and liver of homozygous knockouts, the authors detected no IDE, and in heterozygotes, they found levels to be about half that of wild-type mice. The authors then measured accumulation of Aβ peptides in the brain over a 20-week period. Animals without IDE accumulated almost twice as much Aβ40 and Aβ42 (1.7 pg/mol and 0.56 pg/mol, respectively) as did control animals (1.05 and 0.39 pg/mol, respectively), while heterozygotes accumulated intermediate levels (1.40 and 0.48 pg/mol, respectively). The results were statistically significant and similar to those of Farris et al. Also similar was that Miller’s team found animals lacking IDE accumulated, by over sixfold, C-terminal fragments of the amyloidβ precursor protein, also called AICD.
The intermediate accumulations seen in the heterozygote animals suggest that IDE activity is the rate-limiting step in the removal of Aβ peptides. "Thus," the authors write, "polymorphisms that result in even modest decreases in insulysin activity are predicted to result in increased Aβ accumulation…[and] furthermore, the ~50 percent decrease in insulysin mRNA, protein, and activity in the heterozygote IDE +/- gene-trap mice relative to wild-type littermates indicates that there is no compensatory mechanism to increase insulysin expression."—Tom Fagan
- Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S. 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.
- Miller BC, Eckman EA, Sambamurti K, Dobbs N, Chow KM, Eckman CB, Hersh LB, Thiele DL. Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6221-6. PubMed.