Low-Dose Lithium Supplementation Influences GSK3β Activity in a Brain Region Specific Manner in C57BL6 Male Mice

Article type: Research Article

Authors: Fenech, Rachel K.^a | Hamstra, Sophie I.^b | Finch, Michael S.^a | Ryan, Chantal R.^a | Marko, Daniel M.^a | Roy, Brian D.^b | Fajardo, Val A.^b | MacPherson, Rebecca E.K.^{a; c; *}

Affiliations: [a] Department of Health Sciences, Brock University, St. Catharines, ON, Canada | [b] Department of Kinesiology, Brock University, St. Catharines, ON, Canada | [c] Centre for Neuroscience, Brock University, St Catharines, ON, Canada

Correspondence: [*] Correspondence to: Rebecca E.K. MacPherson, PhD, Brock University, Department of Health Sciences, Faculty of Applied Health Sciences, St. Catharines ON, L2S 3A1, Canada. E-mail: rmacpherson@brocku.ca.

Abstract: Background:Lithium, a commonly used treatment for bipolar disorder, has been shown to have neuroprotective effects for other conditions including Alzheimer’s disease via the inhibition of the enzyme glycogen synthase kinase-3 (GSK3). However, dose-dependent adverse effects of lithium are well-documented, highlighting the need to determine if low doses of lithium can reliably reduce GSK3 activity. Objective:The purpose of this study was to evaluate the effects of a low-dose lithium supplementation on GSK3 activity in the brain of an early, diet-induced Alzheimer’s disease model. Methods:Male C57BL/6J mice were divided into either a 6-week or 12-week study. In the 6-week study, mice were fed a chow diet or a chow diet with lithium-supplemented drinking water (10 mg/kg/day) for 6 weeks. Alternatively, in the 12-week study, mice were fed a chow diet, a high-fat diet (HFD), or a HFD with lithium-supplemented drinking water for 12 weeks. Prefrontal cortex and hippocampal tissues were collected for analysis. Results:Results demonstrated reduced GSK3 activity in the prefrontal cortex as early as 6 weeks of lithium supplementation, in the absence of inhibitory phosphorylation changes. Further, lithium supplementation in an obese model reduced prefrontal cortex GSK3 activity as well as improved insulin sensitivity. Conclusion:Collectively, these data provide evidence for low-dose lithium supplementation to inhibit GSK3 activity in the brain. Moreover, these results indicate that GSK3 activity can be inhibited despite any changes in phosphorylation. These findings contribute to an overall greater understanding of low-dose lithium’s ability to influence GSK3 activity in the brain and its potential as an Alzheimer’s disease prophylactic.

Keywords: Alzheimer’s disease, brain, GSK3, insulin, lithium

DOI: 10.3233/JAD-220813

Journal: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 615-626, 2023