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

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Min-Ju KimSangmee Ahn Jo

Abstract

Proteolytic processing of amyloid peptides (Aβs) is one important mechanism that controls the brain Aβ level. Although several Aβ-degrading enzymes were identified, evidence has suggested the presence of other peptidases. Here, we report a novel function of glutamate carboxypeptidase II (GCPII) in Aβ 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 Aβ1-40 and Aβ1-42 monomers at their C-termini, producing smaller fragments, and Aβ1-14 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 Aβs and reduced Aβ-induced neurotoxicity, suggesting the biological significance of GCPII-mediated Aβ cleavage. Moreover, treatment of 8-mo-old transgenic mice for 1 mo with 2-(phosphonomethyl)-pentanedioic acid (10 mg/kg, intraperitoneall...Continue Reading

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Citations

Jul 31, 2013·Biochemical and Biophysical Research Communications·Suk Kyung LeeSang Ick Park
Nov 30, 2011·Journal of Neurochemistry·Natalia N NalivaevaAnthony J Turner
May 1, 2012·Biomolecules & Therapeutics·Sang-Sun Yoon, Sangmee Ahn Jo
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Mar 26, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·František SedlákJan Konvalinka
Mar 26, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jesse AltBarbara Slusher
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