| First Author | Kim MJ | Year | 2010 |
| Journal | FASEB J | Volume | 24 |
| Issue | 11 | Pages | 4491-502 |
| PubMed ID | 20624932 | Mgi Jnum | J:196634 |
| Mgi Id | MGI:5488883 | Doi | 10.1096/fj.09-148825 |
| Citation | Kim MJ, et al. (2010) Glutamate carboxypeptidase II: an amyloid peptide-degrading enzyme with physiological function in the brain. FASEB J 24(11):4491-502 |
| abstractText | Proteolytic processing of amyloid peptides (Abetas) is one important mechanism that controls the brain Abeta level. Although several Abeta-degrading enzymes were identified, evidence has suggested the presence of other peptidases. Here, we report a novel function of glutamate carboxypeptidase II (GCPII) in Abeta 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 Abeta1-40 and Abeta1-42 monomers at their C-termini, producing smaller fragments, and Abeta1-14 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)-1DeltaE9 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 Abetas and reduced Abeta-induced neurotoxicity, suggesting the biological significance of GCPII-mediated Abeta 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 Abeta content. These results suggest an important physiological role for GCPII in Abeta clearance in brain and provide the evidence that dysregulation of GCPII is involved in Alzheimer's disease pathology. |
