LIPOPROTEIN LIPASE DEFICIENCY AND HUMAN BRAIN FUNCTION

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DESCRIPTION: (adapted from applicant's abstract) Lipoprotein lipase (LPL) plays a crucial role in the maturation and homeostasis of plasma lipoproteins. Although LPL gene mutations, leading to inactivation of the enzyme, have been found in different ethnic groups, detailed studies have been carried out mainly among French-Canadians because of the large number of people that have been affected by LPL deficiency in this population. The incidence of homozygosity for LPL deficiency in the North-Eastern region of the Province of Quebec is at least 1 in 10,000 while the incidence in the general population is as low as 1 in 1,000,000. The total number of carriers for LPL mutations is estimated to be at least 45,000 in the province of Quebec. Of the 5 LPL mutations so far detected in Quebec, one (P207L) appears to be unique to this population and is not found elsewhere. LPL appears to have a variety of general as well as tissue specific functions in the nervous system. LPL deficiency in humans has been observed to produce a number of neurological defects, including memory loss, difficulty in clear thinking and problem solving. These functions are usually associated with the hippocampus which is one of the brain structures containing the highest concentrations of LPL. The most serious consequences of this disorder in regard to pathogenesis is probably related to modifications in the sizes and composition of circulating lipoprotein particles and the formation of potentially toxic lipid byproducts. One such modification is a 4 fold increase in the concentration of lyso-phosphatidylcholine (lyso-PTC) which is reported to stimulate the production of interleukins by blood mononuclear cells. In the proposed project, we wish to test the hypothesis that LPL deficiency interferes with the normal processes of communication between the immune and nervous systems, mediated by the interleukins, through structural and functional alterations of both the blood mononuclear cells and brain cells. Our experiments will be carried out using blood cells and plasma derived from LPL deficient and normal French Canadian subjects whose genotypes and phenotypes we have already characterized in detail. In vivo experiments requiring brain tissue will be performed using LPL knockout transgenic mice.