Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease.
Inhibitors of the enzyme acetylcholinesterase (AChE) are presently used as long-term symptomatic treatments for patients with Alzheimer disease (AD), as they enhance central levels of synaptic acetylcholine. The accumulation of evidence implicating AChE in the pathogenesis of AD raises the question of whether, in addition to their palliative actions, inhibitors of this enzyme are able to act as disease-modifying agents. In addition to their catalytic effects, there is a suggestion that AChE inhibitors may influence expression of AChE isoforms and increase expression of nicotinic receptors, both of which correlate with cognitive improvements in AD patients. The neuroprotective effect of nicotine, presumably mediated via nicotinic receptors, against beta-amyloid (Abeta) toxicity and its effect on amyloid precursor protein (APP) and Abeta production has previously been established. It has also been shown that AChE inhibitors influence APP processing and attenuate Abeta-induced toxicity via mechanisms including interruption of the production of Abeta, alteration of the levels of Abeta 1-50 and 1-52, and formation of the soluble form of APP. Some of these effects seem to occur independently of nicotinic receptors, however. If such experimental in vitro observations can be extrapolated into clinical neuroprotective properties, AChE inhibitors could positively modulate the disease course of AD.
Nordberg
Agneta
A
Neurotec Department, Division of Molecular Neuropharmacology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden. Agneta.Nordberg@neurotec.ki.se
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D048448:Phenylcarbamates / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D000068836:Rivastigmine; D013619:Tacrine / Q000627:therapeutic use; D016896:Treatment Outcome
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D011978:Receptors, Nicotinic; D013619:Tacrine; D000109:Acetylcholine; D000068836:Rivastigmine