Amyloidogenic processing of Alzheimer's amyloid precursor protein in vitro and its modulation by metal ions and tacrine.
Recent studies implicate that excessive amyloidogenic pathway of amyloid precursor protein (APP) processing may be the final common pathway involved in the pathogensis of AD. In attempts to identify the proteases or factors leading to excessive amyloid deposition, we evaluated the potential role of acethylcholinesterase (AChE) and its associated protease for amyloidogenic processing of APP in vitro. Prolonged incubation of a recombinant APP770 with AChE produced several amyloidogenic fragments accumulating a relatively stable a 18 kDa A beta (amyloid beta-protein) bearing carboxy terminal peptide, which was further degraded by an increased concentration of AChE. Protease inhibitory profiles confirmed the trypsin-like serine protease activity present in AChE preparation. This observed APP processing was significantly enhanced by Ca2+, Mg2+, or Mn2+ at 1 mM concentration and modulated in concentration dependent manners by metal ions such as Ca2+, Zn2+, Fe2+/Fe3+, Al3+, or a tacrine, a centrally active cholinesterase inhibitor. Our data imply that AChE and its associated protease may be involved in the generation a 18 kDa amyloidogenic peptide under certain physiological condition in vivo and that the gradual changes in their proteolytic activities or locations and the locally disturbed metal homeostasis could be factors associated with abnormal accumulation of APP, eventually leading to amyloid deposition in AD brain. In addition, zinc or tacrine treatment of AD patients with high dosage or in the long term may have effects on the process of amyloidogensis.
Chong
Y H
YH
Department of Microbiology, College of Medicine, Ewha Womans University, Seoul, Korea.
Suh
Y H
YH
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis; D008670:Metals / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013379:Substrate Specificity; D013619:Tacrine / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D008670:Metals; D011480:Protease Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase