A new brain metalloendopeptidase which degrades the Alzheimer ß-amyloid 1-40 peptide producing soluble fragments without neurotoxic effects

• Published in: Brazilian journal of medical and biological research 1997-10, Vol.30 (10), p.1153-1156
• Main Authors: Carvalho, K.M., França, M.S.F., Camarão, G.C., Ruchon, A.F.
• Format: Article
• Language: English
• Subjects: Alzheimer ß-amyloid 1-40 peptide; Alzheimer's disease; BIOLOGY; brain metalloendopeptidase; MEDICINE, RESEARCH & EXPERIMENTAL
• ISSN: 0100-879X; 1414-431X; 0100-879X; 1414-431X
• DOI: 10.1590/S0100-879X1997001000002

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 ß-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 µM 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 ß-amyloid 1-40 peptide (Km = 5 µM) 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 ß-protein in Alzheimer's disease may be initiated by a defect or an inactivation of this enzyme.