Effect of Memantine Treatment and Combination with Vitamin D Supplementation on Body Composition in the APP/PS1 Mouse Model of Alzheimer’s Disease Following Chronic Vitamin D Deficiency

Article type: Research Article

Authors: Wong, Dickson^{a; b; 1} | Broberg, Dana N.^{a; b; 1} | Doad, Jagroop^a | Umoh, Joseph U.^c | Bellyou, Miranda^a | Norley, Chris J. D.^c | Holdsworth, David W.^{b; c} | Montero-Odasso, Manuel^{d; e; f} | Beauchet, Olivier^g | Annweiler, Cedric^{h; i} | Bartha, Robert^{a; b; *}

Affiliations: [a] Centre for Functional and Metabolic Mapping, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada | [b] Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada | [c] Preclinical Imaging Research Centre, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada | [d] Department of Medicine, Division of Geriatric Medicine, Parkwood Hospital, University of Western Ontario, London, ON, Canada | [e] Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada | [f] Lawson Health Research Institute, London, ON, Canada | [g] Department of Medicine, University of Montreal and McGill University, Montreal, QC, Canada | [h] Department of Geriatric Medicine and Memory Clinic, Research Center on Autonomy and Longevity, University Hospital, Angers, France | [i] UPRES EA 4638, University of Angers, Angers, France

Correspondence: [*] Correspondence to: Robert Bartha, Scientist and Director, Imaging Research Laboratories, Robarts Research Institute, The University of Western Ontario, 1151 Richmond St., London, ON N6A 3K7, Canada. Tel.: +1 519 663 5777 /Ex24039; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Vitamin D deficiency and altered body composition are common in Alzheimer’s disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-β exposure and glutamate toxicity. Objective:To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. Methods:Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n = 14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The vitamin D-deficient group (n = 14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n = 14), while the other had both memantine and 10 IU/g vitamin D (n = 14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. Results:In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p < 0.01) and absolute skeletal tissue mass (9.3% increase, p < 0.05) and volume (9.2% increase, p < 0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. Conclusion:Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD.

Keywords: Adipose tissue, Alzheimer’s disease, animal models, body composition, bone and bones, 3-D imaging, memantine, muscle, vitamin D, x-ray micro-CT

DOI: 10.3233/JAD-201137

Journal: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 375-388, 2021