A new brain metalloendopeptidase which degrades the Alzheimer beta-amyloid 1-40 peptide producing soluble fragments without neurotoxic effects.
A new metalloendopeptidase was purified to apparent homogeneity from a homogenate of normal human brain using successive steps of chromatography on DEAE-Trisacryl, hydroxylapatite and Sephacryl S-200. The purified enzyme cleaved the Gly33-Leu34 bond of the 25-35 neurotoxic sequence of the Alzheimer beta-amyloid 1-40 peptide producing soluble fragments without neurotoxic effects. This enzyme activity was only inhibited by divalent cation chelators such as EDTA, EGTA and o-phenanthroline (1 mM) and was insensitive to phosphoramidon and captopril (1 microM concentration), specific inhibitors of neutral endopeptidase (EC 3.4.24.11) and angiotensin-converting enzyme (EC 3.4.15.1), respectively. The high affinity of this human brain endopeptidase for beta-amyloid 1-40 peptide (Km = 5 microM) suggests that it may play a physiological role in the degradation of this substance produced by normal cellular metabolism. It may also be hypothesized that the abnormal accumulation of the amyloid beta-protein in Alzheimer's disease may be initiated by a defect or an inactivation of this enzyme.
Carvalho
K M
KM
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, Brasil.
França
M S
MS
Camarão
G C
GC
Ruchon
A F
AF
D000328:Adult; D000544:Alzheimer Disease / Q000201:enzymology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000201:enzymology*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans
D016229:Amyloid beta-Peptides; D010450:Endopeptidases