Nicotinic component of galantamine in the regulation of amyloid precursor protein processing.
Current therapies for Alzheimer's disease treatment rely mainly on acetylcholinesterase inhibitors, improving central cholinergic neurotransmission. Among these molecules, galantamine (GAL) has an interesting pharmacological profile as it is both a reversible acetylcholinesterase inhibitor and an allosteric potentiator of nicotinic cholinergic receptors. We investigated the effect of GAL on the metabolism of the amyloid precursor protein (APP) in differentiated SH-SY5Y neuroblastoma cells. The rationale was based on the suggestion that cholinergic activity may also be involved in the regulation of APP metabolism. We studied the acute effect on APP metabolism measuring the secretion of sAPPalpha in the conditioned medium of cells. Following 2h treatment, GAL 10microM promoted a strong increase in the release of sAPPalpha, the maximal effect approaching on average three-fold baseline value. The compound appeared to increase the release of sAPPalpha, with a mechanism dependent upon an indirect cholinergic stimulation. The effect of GAL was prevented by pre-treatment with alpha-bungarotoxin (40nM) but not low (nanomolar) atropine concentrations, suggesting the specific involvement of nicotinic cholinergic receptors.
Lenzken
Silvia C
SC
Department of Experimental and Applied Pharmacology, Centre of Excellence in Applied Biology, University of Pavia, Viale Taramelli 14, CAP 27100 Pavia, Italy.
Lanni
Cristina
C
Govoni
Stefano
S
Lucchelli
Adele
A
Schettini
Gennaro
G
Racchi
Marco
M
D000110:Acetylcholinesterase / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D017077:Culture Media, Conditioned; D011978:Receptors, Nicotinic; D005702:Galantamine; D000110:Acetylcholinesterase