Neurodegenerative diseases constitute one of the most common health problems affecting an increasing number of the elderly population. We have recently examined brains from patients with Alzheimer's disease and, surprisingly, found dramatic alterations in the composition of the membrane lipids in these brains. Investigations on the brain lipids, particularly of the mevalonate pathway lipids, is a relatively new field, mainly because the necessary methodology has only recently been developed. To examine the pathogenetic importance of changes in membrane lipids for the development of neurodegeneration, an experimental animal model is required. Genetic prion diseases in laboratory animals display the same neuropathological features as the corresponding human neurodegenerative diseases. This is true both infectious scrapie infection in rodents and for the spontaneous neurodegenerative diseases occurring in transgenic mice with a mutation in the prion protein. These models lend themselves to kinetic studies of the development of the neurodegenerative process during the entire disease period. The investigation will be focused on phospholipid structure, especially on the modification of polyunsaturated fatty acid content; on modification in the structures and amounts of the mevalonate pathway lipids, primarily dolichol and dolichyl-phosphate; and on the oxidation- reduction state of the only endogenous antioxidant in the living cell, ubiquinone. Dolichly-phosphate participates in oligosaccharide biosynthesis and these structures are known to be involved in the development of neurodegenerative diseases The various oligosaccharide associated with dolichyl-phosphate and the nature and the amount of covalently bound dolichyl-phosphate will be analyzed in detail. Our studies to date indicate that the phosphomethyltransferase plays a role in the degenerative process, which is also the case for the phosphatidylinositol anchor of various membranes. A number of methods will be applied to modify membrane lipid structures, both in vitro and in vivo systems, with an aim to examine the primary importance of lipid changes in the pathogenesis of the disease and to develop possible therapeutic approaches for inerfering with degenerative process.
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