Hypomorphic apolipoprotein E mice: a new model of conditional gene repair to examine apolipoprotein E-mediated...

In creating an allelic variant of mouse Apoe designed to resemble human apolipoprotein E4 (apoE4), we generated hypomorphic apoE (hypoE) mice that express only approximately 5% of normal apoE mRNA levels in all tissues. Insertion of a neo cassette flanked by loxP sites in the third intron of Apoe reduced expression of the Arg-61 allelic variant in hypoE mice and resulted in plasma apoE levels that were approximately 2-5% of normal. Unlike other mouse models with low levels of circulating apoE, hypoE mice had a nearly normal lipoprotein cholesterol profile when fed a chow diet. Further reduction of apoE expression in hypoE/Apoe(-/-) heterozygous mice led to an increase in remnant lipoprotein-associated cholesterol levels, demonstrating that hypoE mice express close to the threshold level of Arg-61 apoE required for a normal lipoprotein profile. Unlike wild type mice, hypoE mice were susceptible to diet-induced hypercholesterolemia, which was fully reversed within 3 weeks after resumption of a chow diet. In Mx1-Cre transgenic hypoE mice, plasma apoE levels returned to normal within 10 days after gene repair and removal of the neo cassette following induction of Cre recombinase. HypoE mice provide the opportunity for conditional gene repair by crossing with inducible or lineage/cell type-specific Cre transgenic mice, generating new models to dissect the roles of apoE in atherosclerosis regression, immunoregulation, and neurodegeneration.