Effects of Memantine and High Dose Vitamin D on Gait in Male APP/PS1 Alzheimer’s Disease Mice Following Vitamin D Deprivation

Article type: Research Article

Authors: Broberg, Dana N.^{a; b; 1} | Wong, Dickson^{a; b; 1} | Bellyou, Miranda^a | Montero-Odasso, Manuel^{c; d; e} | Beauchet, Olivier^{f; g} | Annweiler, Cedric^{h; i; j} | Bartha, Robert^{a; b; *}

Affiliations: [a] Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, Canada | [b] Department of Medical Biophysics, University of Western Ontario, London, ON, Canada | [c] Department of Medicine and Division of Geriatric Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada | [d] Gait and Brain Lab, Parkwood Institute, Lawson Health Research Institute, London, ON, Canada | [e] Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada | [f] Department of Medicine and Geriatrics, University of Montreal, Montreal, QC, Canada | [g] Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore | [h] Department of Geriatric Medicine and Memory Clinic, Research Center on Autonomy and Longevity, University Hospital, Angers, France | [i] UNIV ANGERS, UPRES EA 4638, University of Angers, Angers, France | [j] Gérontopôle Autonomie Longévité des Pays de la Loire, Nantes, France

Correspondence: [*] Correspondence to: Robert Bartha, Robarts Research Institute, Western University, 1151 Richmond Street, London, ON N6A 5B7, Canada. Tel.: +1 519 661 2111 /Ext 24039; E-mail: [email protected].

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

Abstract: Background:Altered gait is a frequent feature of Alzheimer’s disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. Objective:Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. Methods:Male APPswe/PS1dE9 mice were split into four groups (n = 14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups started a vitamin D-deficient diet at month 6. One group remained on this deficient diet for the rest of the study. At month 9, the other two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait was assessed using CatWalk at months 6, 9, 12, and 15. Results:Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p < 0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p < 0.01), while mice treated with memantine and vitamin D did not (p = 0.21). Conclusion:Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD.

Keywords: Alzheimer’s disease, animal model, CatWalk, gait, memantine, vitamin D

DOI: 10.3233/JAD-215188

Journal: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1755-1766, 2022