Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer’s disease

Abstract

BackgroundIncreasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer’s disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates. We first performed a kinematic behavioural examination at 4, 6 and 8 months of age (M4, M6 and M8) followed by a histologic assessment of AD markers. We then performed a comparative transcriptomic analysis of mRNA regulation in the neocortex and hippocampus of 9 months old (M9) female mice.ResultsTranscriptomic analysis of the hippocampus and neocortex of both Wt and Tg mice at M9, following 5 months of vitamin D3 treatment, reveals a large panel of dysregulated pathways related to i) immune and inflammatory response, ii) neurotransmitter activity, iii) endothelial and vascular processes and iv) hormonal alterations. The differentially expressed genes are not all direct targets of the vitamin D-VDR pathway and it appears that vitamin D action engages in the crosstalk with estrogen and insulin signaling. The misexpression of the large number of genes observed in this study translates into improved learning and memory performance and a decrease in amyloid plaques and astrogliosis in Tg animals.ConclusionsThis study underlies the multiplicity of action of this potent neurosteroid in an aging and AD-like brain. The classical and non-classical actions of vitamin D3 can act in an additive and possibly synergistic manner to induce neuroprotective activities in a context-specific way.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0087-2) contains supplementary material, which is available to authorized users.

The Effects of Vitamin D Deficiency on Neurodegenerative Diseases

“…A study from Landel et al examined the transcriptome of 5xFAD mice after 5 months of vitamin D 3 supplementation and reported a large number of differentially expressed genes. The authors suggest an interaction of vitamin D with estrogen and insulin signaling to regulate the identified pathways [62]. Consistently, we could show that a deficit of vitamin D causes a dysregulation of numerous genes that are involved in multiple cellular processes like neurogenesis, inflammation, mitochondrial function, oxidative stress, signal transduction, and APP homeostasis in brains of hypovitaminosis D mice [63].…”

“…Causal link [63] Transcription [62] Causal relationship [63] Regulatory T cells ↑ [112] Vit. D2 as suitable therapeutic candidate [128] Potential role of the VDR [138] Benefits after supplementation [139,140] Vit [92] Immunomodulatory effects [113] Ca 2+ homeostasis [114] Reduced oligomerization of prions [128] Inflammation [141] Ca 2+ homeostasis [142] Potential transcriptional regulation of HTT gene [150] Intervention studies Beneficial [58] Beneficial in dependence of genotype [87] Beneficial [115][116][117][118] Vit.…”

Effects of vitamin D in the nervous system: Special focus on interaction with steroid hormone signalling and a possible role in the treatment of brain cancer

“…Landel et al carried out a transcriptomic analysis of mRNA regulation in thw brains of vitamin D‐treated 5XFAD transgenic mice, a murine model for Alzheimer's disease, and reported the dysregulation of pathways that are targets of oestrogen‐ and insulin‐induced signalling. Long‐term vitamin D 3 supplementation induced the dysregulation of a large number of genes, related to many biological pathways, in both transgenic and wild‐type mice.…”

Calcitriol increases frataxin levels and restores altered markers in cell models of Friedreich Ataxia

“…Alzheimer disease by reducing the levels of amyloid beta protein [56,57] or decrease neurotoxic events in animal models of Parkinson disease [58]. Also vitamin D contributes to neuroprotection [59] and prevents cognitive decline in aged brain [60].…”