In the December 2 online Journal of Biological Chemistry, researchers extend to mice earlier in-vitro observations linking Aβ degradation to the activity of endothelin converting enzyme (ECE). This membrane-bound metalloproteinase, best known for activation of the vasoconstrictor endothelin, has been shown previously to hydrolyze synthetic Aβ, and the ECE inhibitor phosphoramidon increases Aβ secretion by cultured cells. Now, Chris Eckman and colleagues at the Mayo Clinic Jacksonville, Florida, have analyzed mouse knockouts of both ECE-1 and ECE-2 isoforms, which have yielded some interesting phenotypes.

In the simplest sense, the Aβ deposition seen in Alzheimer's disease could be caused by either overproduction of Aβ or a failure to adequately clear normally produced protein. The phenotype of the ECE knockout mice suggests the latter. Though mice heterozygous for the ECE-1 null mutation had only a 27 percent reduction in converting enzyme activity, this was accompanied by an increase in brain Aβ levels. While modest, i.e., increasing from 1.11 pmol/g to 1.34 pmol/g, it was statistically significant, and comparable to elevations seen in AD cases. In addition, the authors failed to detect any increase in levels of Aβ precursor protein (AβPP) or of the AβPP C-terminal fragments that are generated when Aβ is formed. Similar results were obtained from non-lethal homozygous ECE-2 knockout mice. The authors conclude that AβPP production and processing are normal in these animals, leaving poor degradation or clearance as the reason for the observed increase of Aβ.

This work adds to the growing literature supporting the idea that Aβ degradation may have gone awry in AD (see related news story). It also carries a cautionary note because, as the authors point out, ECE inhibitors are being studied as potential drugs for hypertension and other ailments, and any potential side effect of increasing Aβ levels may go undetected for years.-Tom Fagan.

Reference:
Eckman EA, Watson M, Marlow L, Sambamurti MK, Eckman CB. Alzheimer's amyloid-β peptide (Aβ) is increased in mice deficient in endothelin-converting enzyme. Journal of Biological Chemistry. 2 December 2002. Abstract

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  1. [Re: Whether there is any data correlating ECE levels and age in humans] The simple answer is that it hasn't yet been examined. The regulation of ECE expression is complex, as evidenced by the production of multiple isoforms of both ECE-1 and ECE-2 through the use of multiple promoters and alternative splicing. Thus, a comprehensive approach to examine each of the isoforms may be necessary, and this is now under way in our laboratory. The complex regulation of ECE activity and the influence of ECE on Aβ levels suggests that physiological conditions that cause a reduction in ECE activity in the brain may elevate Aβ levels and increase susceptibility to AD. Reductions in ECE activity in the brain (either in total activity or in the relative expression of ECE isoforms) may occur in normal aging, the most common risk factor for AD. Equally important, however, is the possibility that there may be individuals with normally high levels of ECE activity who are at a reduced risk for the disease. To address these issues we are also examining the ECE expression and enzymatic activity in human brain and determining whether these measures correlate with the amount of soluble and/or insoluble Aβ present in normal individuals, individuals with mild cognitive impairment (MCI), individuals with autopsy-confirmed AD, and individuals with other neurological diseases. You can read more about ECE and Aβ in a recent review of ours, available in preprint form (Chapter 7).

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References

News Citations

  1. Stockholm: Degradation on the Rise

Paper Citations

  1. . Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. J Biol Chem. 2003 Jan 24;278(4):2081-4. PubMed.

Further Reading

Papers

  1. . Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. J Biol Chem. 2003 Jan 24;278(4):2081-4. PubMed.

News

  1. Fog Beginning to Clear on Aβ-Degrading Enzymes?

Primary Papers

  1. . Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. J Biol Chem. 2003 Jan 24;278(4):2081-4. PubMed.