Glutamate carboxypeptidase II: an amyloid peptide-degrading enzyme with physiological function in the brain

초록

Proteolytic processing of amyloid peptides (A beta s) is one important mechanism that controls the brain A beta level. Although several A beta-degrading enzymes were identified, evidence has suggested the presence of other peptidases. Here, we report a novel function of glutamate carboxypeptidase II (GCPII) in A beta degradation in brain, which is a peptidase involved in N-acetylaspartylglutamate cleavage, folate metabolism, and prostate tumorigenesis. Maldi-Tof/MS analysis showed that recombinant human GCPII cleaved the A beta 1-40 and A beta 1-42 monomers at their C-termini, producing smaller fragments, and A beta 1-14 that lacked aggregation property and cellular toxicity. GCPII also degrades soluble oligomers and fibrils and can reduce the endogenous plaque size in brain sections obtained from amyloid precursor protein (APP) Swedish/presinilin (PS)-1 Delta E9 transgenic mice. Overexpression of GCPII in either HEK293-APP Swedish cells or primary neurons and glial cells reduced the levels of secreted or exogenously supplemented A beta s and reduced A beta-induced neurotoxicity, suggesting the biological significance of GCPII-mediated A beta cleavage. Moreover, treatment of 8-mo-old transgenic mice for 1 mo with 2-(phosphonomethyl)-pentanedioic acid (10 mg/kg, intraperitoneally), a specific GCPII inhibitor, increased cerebral A beta content. These results suggest an important physiological role for GCPII in A beta clearance in brain and provide the evidence that dysregulation of GCPII is involved in Alzheimer's disease pathology.-Kim, M.-J., Chae, S. S., Koh, Y. H., Lee, S. K., Jo, S. A. Glutamate carboxypeptidase II: an amyloid peptide-degrading enzyme with physiological function in the brain. FASEB J. 24, 4491-4502 (2010). www.fasebj.org

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