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Glutamate carboxypeptidase II: an amyloid peptide‐degrading enzyme with physiological function in the brain
Author(s) -
Kim MinJu,
Chae San Sook,
Koh Young Ho,
Lee Suk Kyung,
Jo Sangmee Ahn
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-148825
Subject(s) - glutamate carboxypeptidase ii , neurotoxicity , amyloid precursor protein , biochemistry , hek 293 cells , genetically modified mouse , glutamate receptor , microbiology and biotechnology , carboxypeptidase , chemistry , transgene , peptide , p3 peptide , internalization , enzyme , biology , alzheimer's disease , toxicity , cell , medicine , prostate , receptor , genetics , disease , organic chemistry , cancer , gene
Proteolytic processing of amyloid peptides (A²s) is one important mechanism that controls the brain A² level. Although several A²‐degrading enzymes were identified, evidence has suggested the presence of other peptidases. Here, we report a novel function of glutamate carboxypeptidase II (GCPII) in A² 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 A²1–40 and A²1–42 monomers at their C‐termini, producing smaller fragments, and A²1–14 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)‐1ΔE9 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 A²s and reduced A²‐induced neurotoxicity, suggesting the biological significance of GCPII‐mediated A² 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 A² content. These results suggest an important physiological role for GCPII in A² 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