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

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.Electronic supplementary materialThe online version of this article (10.1007/s12035-017-0839-1) contains supplementary material, which is available to authorized users.

Histamine H3 Receptor Antagonist Enhances Neurogenesis and Improves Chronic Cerebral Hypoperfusion-Induced Cognitive Impairments

“…Deficits in adult neurogenesis may underlie the cognitive deficits in numerous neurological disorders such as depression (Sahay and Hen, 2007), Alzheimer's disease (Mu and Gage, 2011), Parkinson's disease (Marxreiter et al, 2013) and stroke (Dillen et al, 2019). Strategies that increase adult neurogenesis have been researched for their therapeutic potential to treat CNS disorders (Zhu et al, 2004;Yau et al, 2014;Hollands et al, 2016;Morello et al, 2018). Inhibition of H3R can protect against traumatic brain injury (TBI)-induced injury by improving neurogenesis (Liao et al, 2019).…”

Neuroinflammation and Neurogenesis in Alzheimer’s Disease and Potential Therapeutic Approaches

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The Effects of Vitamin D Deficiency on Neurodegenerative Diseases

“…In contrast to the missing clinical trials, several animal and cell culture studies underline a causal relationship between vitamin D and AD. One study described an increased neurogenesis and enhanced cognition after feeding a transgenic mouse model of AD (5xFAD mouse model) with a daily dose of 500 IU/kg vitamin D for 5 months [59]. Additionally, animal and cell culture studies allow analyzing combination therapies, for example, a supplementation of both vitamin D and resveratrol.…”