Affiliations: [a] University of Kansas Alzheimer's Disease Center, University of Kansas School of Medicine, Kansas City, KS, USA | [b] Departments of Neurology, University of Kansas School of Medicine, Kansas City, KS, USA | [c] Physical Therapy and Rehabilitation Sciences, University of Kansas School of Medicine, Kansas City, KS, USA | [d] Molecular and Integrative Physiology, University of Kansas School of Medicine, Kansas City, KS, USA | [e] Biochemistry and Molecular Biology, University of Kansas School of Medicine, Kansas City, KS, USA
Correspondence:
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Correspondence to: Russell H. Swerdlow, MD, University of Kansas School of Medicine, MS 2012, Landon Center on Aging, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Tel.: +1 913 588 6970; Fax: +1 913 945 5035; E-mail: [email protected].
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.
