A protease activity associated with acetylcholinesterase releases the membrane-bound form of the amyloid protein precursor of Alzheimer's disease.
Amyloid deposits in the brains of patients with Alzheimer's disease (AD) contain a protein (beta A4) which is abnormally cleaved from a larger transmembrane precursor protein (APP). APP is believed to be normally released from membranes by the action of a protease referred to as APP secretase. Amyloid deposits have also been shown to contain the enzyme acetylcholinesterase (AChE). In this study, a protease activity associated with AChE was found to possess APP secretase activity, stimulating the release of a soluble 100K form of APP from HeLa cells transfected with an APP cDNA. The AChE-associated protease was strongly and specifically inhibited by soluble APP (10 nM) isolated from human brain. The AChE-associated protease cleaved a synthetic beta A4 peptide at the predicted cleavage site. As AChE is decreased in AD, a deficiency of its associated protease might explain why APP is abnormally processed in AD.
Small
D H
DH
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Moir
R D
RD
Fuller
S J
SJ
Michaelson
S
S
Bush
A I
AI
Li
Q X
QX
Milward
E
E
Hilbich
C
C
Weidemann
A
A
Beyreuther
K
K
D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000201:enzymology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000494:pharmacology; D007611:Aprotinin / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D002462:Cell Membrane / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D011480:Protease Inhibitors; D007611:Aprotinin; D000110:Acetylcholinesterase; D010450:Endopeptidases