Neurological disorders such as Alzheimer's disease (AD), and to a lesser extent normal aging, are associated with declines in motor and cognitive behavior. There is a strong need to identify those modifiable factors that regulate the proper maintenance of those brain regions involved in controlling behavior. Dysregulation of sulfatides, a subclass of spingolipids in the brain, is a risk factor for cognitive dysfunction observed in AD and normal aging. We propose to initiate a series of novel animal studies that examine the role of dietary interventions, which are potentially modifiable, on sulfatide metabolism. Vitamin K is present in high concentrations in the brain, and has been implicated in a positive regulation of sulfatide metabolism. The primary objectives of the proposed study are to develop a novel animal model for the study of the interplay between vitamin K and sulfatides in brain regions controlling motor and cognitive behavior, and to determine if age and sex-specific differences in vitamin K status influence sulfatide metabolism. Vitamin K and sulfatides status will be assessed in myelin (axon insulator) and synaptosomes (nerve terminals), isolated from the cortex, hippocampus and striatum of Fischer 344 rats (n=80), following 28 days of intake of 500 ?g/kg of diet of one of two forms of vitamin K [phylloquinone (K1) or dihydrophylloquinone (dK)]. There is a tissue-specific conversion of K1 to menaquinone-4 (MK-4), which is the major form of vitamin K in the brain. Conversely, there is no conversion of dK to MK-4 in the brain, nor is there accumulation of dK in the brain. The proposed study will exploit this inability of dK to convert to MK-4 to develop a novel animal model that can manipulate vitamin K status in the brain, while conserving vitamin K-dependent coagulation. We will apply this model to examine the role of age (2m, 12m, and 24m) and gender on vitamin K and sulfatide metabolism. These studies will provide the foundation for future studies on the role of dietary vitamin K in sphingolipid metabolism as it relates to healthy aging, and ultimately its role in motor and cognitive behavior. ? ?
| Crivello, Natalia A; Casseus, Sherley L; Peterson, James W et al. (2010) Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides. J Nutr Biochem 21:1083-8 |
| Booth, Sarah L; Peterson, James W; Smith, Donald et al. (2008) Age and dietary form of vitamin K affect menaquinone-4 concentrations in male Fischer 344 rats. J Nutr 138:492-6 |
