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

authors

• Morello Maria
• Landel Véréna
• Lacassagne Emmanuelle
• Baranger Kévin
• Annweiler Cédric
• Féron François
• Millet Pascal

keywords

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

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.

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