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

RESUMO

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 Gly(33)-Leu(34) 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, AGTA and o-phenanthroline (1 mM) and was insensitive to phosphoramidon and captopril (1 muM 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 muM) 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.