title: Effect of cholinergic signaling on neuronal cell bioenergetics.
abstract: Alzheimer's disease (AD) patients have reduced brain acetylcholine and reversing this deficit yields clinical benefits. In this study we explored how increased cholinergic tone impacts cell bioenergetics, which are also perturbed in AD. We treated SH-SY5Y neuroblastoma cells with carbachol, a cholinergic agonist, and tested for bioenergetic flux and bioenergetic infrastructure changes. Carbachol rapidly increased both oxidative phosphorylation and glycolysis fluxes. ATP levels rose slightly, as did cell energy demand, and AMPK phosphorylation occurred. At least some of these effects depended on muscarinic receptor activation, ER calcium release, and ER calcium re-uptake. Our data show that increasing cholinergic signaling enhances cell bioenergetics, and reveal mechanisms that mediate this effect. Phenomena we observed could potentially explain why cholinesterase inhibitor therapy increases AD brain glucose utilization and N-acetyl aspartate levels. The question of whether cholinesterase inhibitors have a disease modifying effect in AD has long been debated; our data suggest a theoretical mechanism through which such an effect could potentially arise.
authors.affiliation: University of Kansas Alzheimer's Disease Center, University of Kansas School of Medicine, Kansas City, KS 66160, USA.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Lu
authors.forename: Lezi
authors.initials: L
authors.lastname: E
authors.forename: Nairita
authors.initials: N
authors.lastname: Roy
authors.forename: Lewis
authors.initials: L
authors.lastname: Hutfles
authors.forename: Eva
authors.initials: E
authors.lastname: Selfridge
authors.forename: Eric
authors.initials: E
authors.lastname: Funk
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Burns
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D045744:Cell Line, Tumor; D018679:Cholinergic Agonists / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D018679:Cholinergic Agonists; D002217:Carbachol; D000109:Acetylcholine