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A New Way to Degrade Amyloid Protein

In Alzheimer disease, amyloid -protein polymerizes into insoluble fibrils in the brain. Although the extracellular accumulation of these plaques has been the focus of most molecular studies associated with Alzheimer disease, lately, increasing attention has focused on intracellular events, including the role of the mitochondria in the disease.

Model of hPreP with amyloid -protein bound to the active site.

In this Paper of the Week, Annelie Falkevall and colleagues report that a novel mitochondrial metalloendopeptidase named presequence protease, or PreP, degrades amyloid -protein. They show that the human PreP (hPreP) is localized to the mitochondrial matrix in mammals where it degrades amyloid -protein. The researchers produced recombinant hPreP and characterized its proteolytic activity both in situ and in vitro. Anti-hPreP antibodies caused complete inhibition of proteolytic activity against amyloid -protein indicating that hPreP is responsible for degrading amyloid -protein when it is present in the mitochondria. Finally, the researchers investigated the degradation pattern of the amyloid -protein using mass spectrometric analysis and found that several unique cleavage sites were used by hPreP. These results indicate that mitochondrial degradation of amyloid -protein by hPreP may be important in the pathology of Alzheimer disease.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 29096-29104

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