Role of acetylcholinesterase inhibitors in the metabolism of amyloid precursor protein.
Potentiation of central cholinergic activity has been proposed as a therapeutic approach for improving the cognitive function in patients with Alzheimer's disease (AD). Increasing the acetylcholine concentration in the brain by modulating acetylcholine-sterase (AChE) activity is among the most promising therapeutic strategies. Efforts to treat the underlying pathology based on the modulation of amyloid precursor protein (APP) processing in order to decrease the accumulation of beta-amyloid are also very important. Alterations in APP metabolism have recently been proposed to play a key role in the long-lasting effects of AChE inhibitors. This review surveys recent data from in vivo and in vitro studies that have contributed to our understanding of the role of AChE inhibitors in APP processing. The regulatory mechanisms relating to the muscarinic agonist effect, protein kinase C activation and mitogen-activated protein kinase phosphorylation, involving the alpha-secretase or the 5 -UTR region of the APP gene, are also discussed. Further work is warranted to elucidate the exact roles in APP metabolism of the AChE inhibitors used in AD therapy at present.
Pakaski
M
M
Alzheimer's Disease Research Centre, Department of Psychiatry, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, Faculty of Medicine, University of Szeged, Hungary. pakaski@comser.szote-u.szeged.hu
Kasa
P
P
D000110:Acetylcholinesterase / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000639:trends; D005544:Forecasting; D006801:Humans; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase