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Mol Neurobiol. 2018 Aug;55(8):6463-6479. doi: 10.1007/s12035-017-0839-1. Epub 2018 Jan 9.

Vitamin D Improves Neurogenesis and Cognition in a Mouse Model of Alzheimer's Disease.

Author information

1
Aix Marseille Univ, CNRS, NICN, Marseille, France.
2
Clinical Biochemistry, Department of Experimental Medicine and Surgery, Faculty of Medicine, University Hospital of Tor Vergata, Rome, Italy.
3
Division of Clinical Nutrition and Nutrigenomics, Department of Biomedicine and Prevention Faculty of Medicine, University of Tor Vergata, Rome, Italy.
4
Department of Neurosciences and Aging, Division of Geriatric Medicine, Angers University Hospital, Angers University Memory Clinic, Research Center on Autonomy and Longevity, UPRES EA 4638, University of Angers, UNAM, Angers, France.
5
Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada.
6
Aix Marseille Univ, CNRS, NICN, Marseille, France. francois.feron@univ-amu.fr.
7
Aix Marseille Univ, CNRS, NICN, Marseille, France. pascal.millet@univ-amu.fr.

Abstract

The impairment of hippocampal neurogenesis at the early stages of Alzheimer's disease (AD) is believed to support early cognitive decline. Converging studies sustain the idea that vitamin D might be linked to the pathophysiology of AD and to hippocampal neurogenesis. Nothing being known about the effects of vitamin D on hippocampal neurogenesis in AD, we assessed them in a mouse model of AD. In a previous study, we observed that dietary vitamin D supplementation in female AD-like mice reduced cognitive decline only when delivered during the symptomatic phase. With these data in hand, we wondered whether the consequences of vitamin D administration on hippocampal neurogenesis are stage-dependent. Male wild-type and transgenic AD-like mice (5XFAD model) were fed with a diet containing either no vitamin D (0VD) or a normal dose of vitamin D (NVD) or a high dose of vitamin D (HVD), from month 1 to month 6 (preventive arm) or from month 4 to month 9 (curative arm). Working memory was assessed using the Y-maze, while amyloid burden, astrocytosis, and neurogenesis were quantified using immunohistochemistry. In parallel, the effects of vitamin D on proliferation and differentiation were assayed on primary cultures of murine neural progenitor cells. Improved working memory and neurogenesis were observed when high vitamin D supplementation was administered during the early phases of the disease, while a normal dose of vitamin D increased neurogenesis during the late phases. Conversely, an early hypovitaminosis D increased the number of amyloid plaques in AD mice while a late hypovitaminosis D impaired neurogenesis in AD and WT mice. The observed in vivo vitamin D-associated increased neurogenesis was partially substantiated by an augmented in vitro proliferation but not an increased differentiation of neural progenitors into neurons. Finally, a sexual dimorphism was observed. Vitamin D supplementation improved the working memory of males and females, when delivered during the pre-symptomatic and symptomatic phases, respectively. Our study establishes that (i) neurogenesis is improved by vitamin D in a male mouse model of AD, in a time-dependent manner, and (ii) cognition is enhanced in a gender-associated way. Additional pre-clinical studies are required to further understand the gender- and time-specific mechanisms of action of vitamin D in AD. This may lead to an adaptation of vitamin D supplementation in relation to patient's gender and age as well as to the stage of the disease.

KEYWORDS:

Alzheimer’s disease; In vitro and in vivo neurogenesis; Memory; Mouse model; Sexual dimorphism; Vitamin D deficiency; Vitamin D supplementation

PMID:
29318446
PMCID:
PMC6061182
DOI:
10.1007/s12035-017-0839-1
[Indexed for MEDLINE]
Free PMC Article

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