CEREBRAL LIPID DEPOSITION IN AGED APOLIPOPROTEIN-E-DEFICIENT MICE

To assess the influence of age and diet on cerebral pathology in mice lacking apolipoprotein E (apoE), four male apoE knockout mice (epsilon -/-), and five male wild-type (epsilon+/+) littermate controls were pl aced on a high-fat/high-cholesterol diet for 7 weeks beginning at 17 m onths of age. All four aged knockout mice developed xanthomatous lesio ns in the brain consisting mostly of crystalline cholesterol clefts, l ipid globules, and foam cells, Smaller xanthomas were confined mainly to the choroid plexus and ventral fornix in the roof of the third vent ricle, occasionally extending subpially along the choroidal fissure an d into the adjacent parenchyma, More advanced xanthomas disrupted adjo ining neural tissue in the fornix, hippocampus, and dorsal diencephalo n; in one case, over 60% of one telencephalic hemisphere, including ne arly the entire neocortex, was obliterated by the lesion, No xanthomas were observed in aged wildtype controls fed the high-fat/high-cholest erol diet. Brains from 42 additional animals, fed only conventional ch ow, were examined; 3 of 15 aged (15- to 23-month-old) apoE knockout mi ce developed small choroidal xanthomas, In contrast, no lesions were o bserved in five young (2- to 4-month-old) apoE knockout mice or in any wild-type controls between the ages of 2 and 23 months. Our findings indicate that disorders of lipid metabolism can induce significant pat hological changes in the central nervous system of aged apoE knockout mice, particularly those on a high-fat/high-cholesterol diet. It may b e fruitful to seek potential interactions between genetic factors and diet in modulating the risk of Alzheimer's disease and other neurodege nerative disorders in aged humans.