title: Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer's disease.
abstract: BACKGROUND
  Increasing 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.
  
  
  RESULTS
  Transcriptomic 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259, Marseille, 13916, France. verena.landel@univ-amu.fr.
authors.forename: Véréna
authors.initials: V
authors.lastname: Landel
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259, Marseille, 13916, France. pascal.millet@inserm.fr.|APHP, Groupe hospitalier universitaire Saint Louis-Lariboisière-Fernand Widal, Centre Mémoire de Ressources et de Recherche, Hôpital Fernand Widal, Paris, France. pascal.millet@inserm.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Millet
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259, Marseille, 13916, France. kevin.baranger@univ-amu.fr.
authors.forename: Kévin
authors.initials: K
authors.lastname: Baranger
authors.affiliation: Aix Marseille Université, INSERM UMR 1090, TAGC, Marseille, France, Marseille, 13288, France. beatrice.loriod@inserm.fr.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Loriod
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259, Marseille, 13916, France. francois.feron@univ-amu.fr.
authors.forename: François
authors.initials: F
authors.lastname: Féron
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000378:metabolism; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D014807:Vitamin D / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047628:Estrogen Receptor alpha; C519530:insulin-like growth factor-1, mouse; D014807:Vitamin D; D007334:Insulin-Like Growth Factor I