α-Tocopherol Restriction Dysregulates Neurogenesis-Related Gene Expression in Brains of Weanling α-Tocopherol Transfer Protein Knockout Mice (P11-134-19)

Abstract

ObjectivesHumans with vitamin E (α-tocopherol, αT) deficiency develop neurological disorders. Similarly, α-tocopherol transfer protein knockout (Ttpa−/−) mice have low vitamin E status and exhibit neurodegeneration with age. Shifts in the transcriptome may precede behavioral manifestations of vitamin E deficiency, but it is unknown how early abnormalities occur. Aberrations during brain development could have lifelong implications. The study objective was to determine how αT restriction during early-life affects the expression of pre-selected neurogenesis-related genes in the cerebellum (CB) and cerebral cortex (CC) of Ttpa−/− weanlings. MethodsFemale Ttpa+/+ (n = 9) and Ttpa−/− (n = 10) mice were nursed by Ttpa+/−dams until postnatal day 21. Dams were fed AIN-93G diet (75 mg αT/kg diet) during days 1–9 of gestation, and αT-stripped diet for the rest of the study. Homogenized brain tissues from 21 day old weanlings were used to measure αT concentrations via HPLC-PDA. The expression of genes critical for brain development (Rora, Shh), myelination (Plp1, Cntnap1, Mbp, Mobp, Nr1h3), synaptic function (Cplx1, Cplx2, Vamp2, Necab1, Prkcg), and αT cellular uptake (Scarb1) were measured in the CB and CC via real-time qPCR. ResultsαT levels were significantly decreased in brains of Ttpa−/− mice (0.1 ± 0.1 nmol/g) compared to Ttpa+/+ mice (9.8 ± 1.4 nmol/g) (P < 0.001), confirming their low αT status. Rora, Shh, Cntnap1, and Mbp were significantly upregulated (P < 0.05) in both the CB and CC of Ttpa−/− mice, while several genes were only upregulated in one brain region (Plp1 in the CB, Mobp in the CC). Necab1 and Scarb1 were significantly downregulated in the CB of Ttpa−/− mice (P < 0.05). ConclusionsαT restriction during the fetal and postnatal periods alters the expression of neurogenesis-related genes. These findings support a role for αT in brain development. Funding SourcesAbbott Nutrition through the Center for Nutrition, Learning and Memory, University of Illinois, Urbana-Champaign; USDA NIFA Hatch grant (ILLU-698-915); Division of Nutritional Sciences Vision 20/20 Grant Program; Division of Nutritional Sciences Margin of Excellence Research Program.