Role of phospholipids in neurodegenerative diseases

Sammanfattning: Doctoral Dissertation 1997 Clinical Research Center, NOVUM and Department of Neuroscience Karolinska Institutet Stockholm, Sweden The structure and composition of brain phospholipids, including also their ether analogues, were investigated and modifications during neurodegeneration were analysed. In order to improve sensitivity and reproducibility, new HPLC methods were developed for separation and quantitation of phospholipids and plasmalogens, followed by quantitation of fatty acids and aldehydes. Using HPLC with 5 mM ammonium sulphate in the mobile phase, all phospholipids and Iyso compounds could be separated. A new method for quantification of alkenylacyl-, alkylacyl- and diacyl forms of phospholipids was established using derivatization with [3H]acetic anhydride. Separation of the radioactive acetyldiradylglycerides was performed by HPLC. In prion disease, using scrapie-infected mouse brain, no changes in phospholipid structure and composition were found. Dolichol decreased, dolichyl-P increased and antioxidants a-tocopherol and, especially, ubiquinone were greatly increased. Tissue destruction is not elicited by leakage of Iysosomal enzymes. Cardiolipin has an outmost importance for mitochondria and modification of this lipid was suggested in Alzheimer's disease. Cardiolipin amount and fatty acid composition were studied in affected and nonaffected regions of the brain and no greater changes could be found. Total phospholipids in Alzheimer affected regions of the brain exhibited a 20% decrease on a DNA basis. Phosphatidylethanolamine (PE) and phosphatidylcholine were lowered and in PE only the plasmalogen subclass changed. PE-plasmalogen showed a decrease in oleic and polyunsaturated fatty acids and displayed a shift ofthe aldehyde pattern from 18:1 to 18:0. In liposomal systems, plasmalogens effectively protected poly unsaturated fatty acids from iron-induced lipid peroxidation and during the process the vinyl ether function of plasmalogens was consumed. It appears that plasmalogens interfere with the propagation rather than the initiation of lipid peroxidation. 1997 Zhi-Zhong Guan ISBN 91-628-2557-7 Akademitryck AB, Edsbruk 1997