Distinct alterations in phospholipid metabolism in brains of apolipoprotein E-deficient mice

Apolipoprotein E (ApoE) is the major brain lipoprotein and plays an important role in lipid transport. ApoE-deficient mice whose apoE gene has been knocked out have distinct cognitive and neurochemical deficits, and their recovery from brain injury is impaired. In the present study we examined the possibility that the neuronal derangements of apoE-deficient mice are related to impairments in their phospholipid metabolism. This was performed by comparison of the phospholipid, fatty acid, and cholesterol compositions of distinct membranal brain fractions of apoE-deficient and control mice. Analysis of the microsomal membrane fraction P(3) revealed that, in apoE-deficient mice, these membranes contain significantly lower levels of phosphatidylcholine (PC) than those of control mice. This effect was specific to PC and thus resulted in a twofold decrease of the PC to phosphatidylethanolamine (PE) ratio in apoE-deficient mice compared to the corresponding control ratio. In contrast, the cholesterol levels of the microsomal membranes of the two mice were similar, and the fatty acid composition of their PC was unchanged. There were, however, changes in the fatty acid composition of PE and phosphatidylserine (PS), which resulted in a lower ratio of polyunsaturated to saturated fatty acids in PE and in a higher ratio in apoE-deficient mice compared to the corresponding control values. These effects were specific to the microsomal fraction P(3) and were not observed with the brain subcellular membrane fraction P(2), which is composed mainly of plasma and mitochondrial membranes and whose phospholipid, fatty acid, and cholesterol levels were similar in apoE-deficient and control mice. These findings show that apoE deficiency results in specific and intracellular compartment-dependent changes in phospholipid metabolism, which may play an important role in mediating the neuronal effects of apoE.