Implication of novel biochemical property of beta-amyloid

Alzheimer disease (AD) is a heterogeneous disorder with a variety of molecu lar pathologies converging predominantly on abnormal amyloid deposition par ticularly in the brain. beta-Amyloid aggregation into senile plaques is one of the pathological hallmarks of AD. beta-Amyloid is generated by a proteo lytic cleavage of a large membrane protein, amyloid precursor protein (APP) . We have observed a new property of beta-amyloid. The amyloid 1-42 beta fr agment, when aggregated, possesses proteolytic and esterase like activity, in vitro. Three independent methods were used to test the new property of b eta-amyloid, While esterase activity involves imidazole catalysis, proteoly tic activity is consistent with participation of a serine peptidase triad: catalytic Ser, His and Glu (or Asp). Although the amino acid triad is a nec essary requirement for the protease reactivity, it is not sufficient since the secondary structure of the protein significantly contributes to the pro teolytic activity. The ability of beta-amyloid to cleave peptide or ester b onds could be thus responsible for either inactivation of other proteins an d/or APP proteolysis itself. This property may be responsible for early pat hogenesis of AD since there is emerging evidence that non-plaque amyloid is elevated in Alzheimer patients. (C) 2000 Academic Press.