Evidence for D-aspartyl-beta-amyloid secretase activity in human brain.
Alzheimer disease (AD) is characterized neuropathologically by the presence of senile plaques that are composed of the amyloid-beta protein (Abeta). Abeta is an insoluble extracellular deposit consisting of 39-43 amino acids that is cleaved from a larger precursor amyloid-beta-precursor protein (beta-APP). It has been shown that Abeta proteins extracted from amyloid cores of neuritic plaques contain isomerized and/or racemized Asp residues. Therefore, we hypothesized that a specific secretase (s) may exist in the human brain that can cleave a beta-APP peptide bond containing D-Asp at position 1 of the Abeta protein. In the present study, we report data to support the existence of a putative membrane-bound D-beta-secretase that can cleave between L-Met-D-Asp at the 1 position of the Abeta with a pH optimum in the neutral pH range. The specific enzyme activity of soluble extracts from AD samples was 22% higher compared to age-matched controls.
Lee
John M
JM
Department of Pathology and Pharmacology, Loyola University Stritch School of Medicine, Maywood, Illinois, USA.
Petrucelli
Leonardo
L
Fisher
George
G
Ramdath
Sona
S
Castillo
James
J
Di Fiore
M Maddalena
MM
D'Aniello
Antimo
A
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology; D000596:Amino Acids / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009842:Oligopeptides / Q000378:metabolism*; D014020:Tissue Extracts / Q000378:metabolism
D000596:Amino Acids; D016564:Amyloid beta-Protein Precursor; D009842:Oligopeptides; D014020:Tissue Extracts; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human