Ataxia with vitamin E deficiency is caused by mutations in α-tocopherol transfer protein (α-TTP) gene and it can be experimentally generated in mice by α-TTP gene inactivation (α-TTP-KO). This study compared α-tocopherol (α-T) concentrations of five brain regions and of four peripheral organs from 5 months old, male and female, wild-type (WT) and α-TTP-KO mice. All brain regions of female WT mice contained significantly higher α-T than those from WT males. α-T concentration in the cerebellum was significantly lower than that in other brain regions of WT mice. These sex and regional differences in brain α-T concentrations do not appear to be determined by α-TTP expression which was undetectable in all brain regions. All the brain regions of α-TTP-KO mice were severely depleted in α-T. The concentration of another endogenous antioxidant, total glutathione, was unaffected by gender but was decreased slightly but significantly in most brain regions of α-TTP-KO mice. The results show that both gender and the hepatic α-TTP, but not brain α-TTP gene expression are important in determining α-T concentrations within the brain. Interestingly, functional abnormality (ataxia) develops only very late in α-TTP-KO mice in spite of the severe α-tocopherol deficiency in brain starting at an early age.

No abstract

No abstract

No abstract

Apolipoprotein E (apoE) is known to be a risk factor for the incidence of Alzheimer's disease (AD). In addition, vitamin E has been reported to have a role in the treatment of AD. We examined the potential interrelationship between vitamin E and apoE in brain. As the first step, we determined the concentrations of a-tocopherol in selected brain regions of apoE-deficient mice at different ages. The mice were fed normal rodent chow. All regions of the brain in apoE-deficient mice contained less a-tocopherol than control samples at 2.5 months of age, the initial time of study. This trend continued for 9.5 months for most regions except the spinal cord and cerebellum. Tocopherol levels in these latter regions of apoE-deficient animals increased to control levels during the study. Serum a-tocopherol and cholesterol levels were high in the apoE-deficient animals; however, the CNS cholesterol levels were the same in apoE-deficient and control mice. This suggests that 1) the decline in brain a-tocopherol in apoE deficiency is not due to overall alterations in lipid metabolism; and 2) the processing of a-tocopherol in brain follows a separate pathway than that of cholesterol. Subcellular concentrations of a-tocopherol were unaltered by apoE deficiency indicating that intracellular handling of tocopherol is not affected by apoE. ApoE may be an important protein controlling vitamin E levels in specific brain regions. Further understanding of the interactions between apoE and vitamin E could be important in the appropriate use of vitamin E in AD. V V C 2006 Wiley-Liss, Inc.

These data suggest that the processes involved in the entry of tocopherol from blood to the CSF do not discriminate between the alpha and gamma tocopherols. In contrast, alpha tocopherol is highly preferred during the packaging of plasma lipoproteins by the liver. Our data also suggest that alpha and gamma tocopherols will be available to the human brain via transport from blood.

An earlier report from this laboratory showed that tocopherol in human platelets is oxidized when the platelets are incubated in vitro in Tyrode medium with arachidonate (or other oxidants). Arachidonate is a more potent oxidizing agent in 50 mM potassium phosphate buffer at pH 7.4 with 0.1 mM ethylenediaminetetraacetic acid (EDTA) than in Tyrode medium. Forty to fifty percent of total platelet tocopherol was oxidized upon incubation with 40-50 microM arachidonate in the phosphate-buffered medium. The tocopherol oxidation took place within 15 min after the addition of arachidonate. Preincubation of platelets with ascorbate blocked the oxidation of tocopherol. This is one of the first direct in vitro demonstrations of the vitamin E-sparing action of vitamin C in media containing biological cellular material. Other compounds which blocked the oxidation of platelet tocopherol were ascorbyl palmitate, propyl gallate, butylated hydroxytoluene, hydroquinone and glutathione. If ascorbate or glutathione was added after the tocopherol was oxidized to the quinone there was no reversal of the oxidation.

No abstract