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Background Vitamin E (α-tocopherol, α-T) deficiency causes neurological pathologies. α-T supplementation improves outcomes, but the relative bioactivities of dietary natural and synthetic α-T in neural tissues are unknown. Objective The aim was to assess the effects of dietary α-T source and dose on oxidative stress and myelination in adult α-tocopherol transfer protein–null (Ttpa−/− ) mouse cerebellum and spinal cord. Methods Three-week-old male Ttpa−/− mice (n = 56) were fed 1 of 4 AIN-93G–based diets for 37 wk: vitamin E–deficient (VED; below α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+littermates (n = 14) fed AIN-93G (75 mg synthetic α-T/kg diet; CON) served as controls. At 40 wk of age, total and stereoisomer α-T concentrations and oxidative stress markers were determined (n = 7/group). Cerebellar Purkinje neuron morphology and white matter areas in cerebellum and spinal cord were assessed in a second subset of animals (n = 7/group). Results Cerebral cortex α-T concentrations were undetectable in Ttpa−/− mice fed the VED diet. α-T concentrations were increased in NAT (4.6 ± 0.3 nmol/g), SYN (8.0 ± 0.7 nmol/g), and HSYN (8.5 ± 0.3 nmol/g) mice, but were significantly lower than in Ttpa+/+ mice fed CON (27.8 ± 1.9 nmol/g) (P &amp;lt; 0.001). 2R stereoisomers constituted the majority of α-T in brains of Ttpa+/+ mice (91%) and Ttpa−/− mice fed NAT (100%), but were substantially lower in the SYN and HSYN groups (∼53%). Neuroinflammatory genes were increased in the spinal cord, but not cerebellum, of VED-fed animals; NAT, SYN, and HSYN normalized their expression. Cerebellar Purkinje neuron atrophy and myelin pathologies were not visible in Ttpa−/− mice. Conclusions Natural and synthetic α-T supplementation normalized neuroinflammatory markers in neural tissues of 10-mo-old Ttpa−/− mice. α-T prevents tissue-specific molecular abnormalities, which may prevent severe morphological changes during late adulthood.

Natural and Synthetic α-Tocopherol Modulate the Neuroinflammatory Response in the Spinal Cord of Adult Ttpa-null Mice