Implication of novel biochemical property of beta-amyloid.
Alzheimer disease (AD) is a heterogeneous disorder with a variety of molecular pathologies converging predominantly on abnormal amyloid deposition particularly in the brain. beta-Amyloid aggregation into senile plaques is one of the pathological hallmarks of AD. beta-Amyloid is generated by a proteolytic cleavage of a large membrane protein, amyloid precursor protein (APP). We have observed a new property of beta-amyloid. The amyloid 1-42 beta fragment, when aggregated, possesses proteolytic and esterase-like activity, in vitro. Three independent methods were used to test the new property of beta-amyloid. While esterase activity involves imidazole catalysis, proteolytic activity is consistent with participation of a serine peptidase triad: catalytic Ser, His and Glu (or Asp). Although the amino acid triad is a necessary requirement for the protease reactivity, it is not sufficient since the secondary structure of the protein significantly contributes to the proteolytic activity. The ability of beta-amyloid to cleave peptide or ester bonds could be thus responsible for either inactivation of other proteins and/or APP proteolysis itself. This property may be responsible for early pathogenesis of AD since there is emerging evidence that non-plaque amyloid is elevated in Alzheimer patients.
Elbaum
D
D
Laboratory of Biophysical Methods, Nencki Institute of Experimental Biology, Warsaw, Poland. elbaum@nencki.gov.pl
Brzyska
M
M
Bacia
A
A
Alkon
D L
DL
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D004047:Diethyl Pyrocarbonate / Q000494:pharmacology; D004950:Esterases / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010830:Physostigmine / Q000494:pharmacology; D011487:Protein Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D010830:Physostigmine; D004950:Esterases; D003676:Deferoxamine; D004047:Diethyl Pyrocarbonate