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Apoe Targeted Mutation Mice Apoe Targeted Mutation Mice Inactivation of the Apoe gene provides a mouse model for human atherogenesis and diverse applications in studies of lipid transport and metabolism Applications for the Apoe Targeted Lipoprotein Profiles of Normal Mutation Mouse Model and Apoe Targeted Mutation Mice The lack of a functional Apoe gene renders these mice unable to produce a key glycoprotein, apoE (apolipoprotein E), which is essential for the transport and metabolism of lipids. The mice Mice are healthy when born, but have a markedly altered plasma lipid profile compared to normal Normal mice, and rapidly develop atherosclerotic lesions. Numerous potential applications to basic research and drug development include: • Cholesterol/triglyceride transport mech- anisms • Role of apoE in lipoprotein binding to endothelium and the incorporation of lipids into atherosclerotic plaques Mice • Cholesterol reverse transport • Relative contributions of dietary consti- tuents to atherogenesis • Modeling of human apoE-deficiency • Impact of lipid oxidation on cellular lipid Targeted Mutation uptake/metabolism • Role of apoA-I and apoA-IV in lipoprotein Apoe formation and transport • Apoe function in normal and diseased neural Figure 1. Reprinted with permission from the Journal of tissue and nerve repair Clinical Investigation. Kashyap, et al.4 • Gene therapy to replace specific Apoe alleles in Apoe Targeted Mutation Mice • Evaluation of pharmacologic manipulations • Markedly elevated plasma cholesterol levels of atherosclerotic plaque formation (5 times normal) • Development through crossbreeding of • Relatively normal plasma triglyceride levels models for specific research programs in • Shift from the normal distribution of plasma atherosclerosis and CNS disease lipids (cholesterol and triglycerides) from predominantly high density lipoprotein Features of the Apoe Targeted (HDL) complexes to predominately very Mutation Mouse (model APOE) 1,2 low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) • Homozygous for defective Apoe gene complexes2 • Complete absence of apoE glycoprotein • Early and severe spontaneous development of atherosclerotic lesions • Normal reproductive performance in both The absence of apoE has multiple effects on male and female Apoe Targeted Mutation lipid metabolism and transport. In normal Mice2 mice, the profile of cholesterol-containing • No reported difference in body weights or plasma lipoproteins includes an abundance of litter size compared to normal mice high density lipoprotein (HDL) and only trace • Enrichment of VLDL and IDL particles with amounts of lower-density lipoproteins (VLDL, 2,3 apoA-I, apoA-IV, and apoB-48, similar to IDL, LDL). In contrast, Apoe Targeted their distribution in humans who are apoE Mutation Mice have the reverse distribution: deficient, and similar to chylomicron 80% of serum cholesterol is sequestered in lower remnants2 density lipoproteins, while HDL-cholesterol is half the normal level.2 In addition, total Scientific Profile of the Apoe cholesterol levels in plasma of Apoe Targeted Targeted Mutation Mouse Model Mutation mice are up to five times that of normal mice (e.g., 434 mg/dl versus 86 mg/dl, 2 Apoe Targeted Mutation Mice are respectively). Thus, both the quantity of homozygous for a defective Apoe gene, and cholesterol and its distribution among apoE protein is absent from blood of these lipoprotein fractions are shifted in the mutant animals.1 Plasma lipoproteins in which apoE mice to a pattern known to be associated in normally is an integral part (e.g., VLDL, IDL, humans with risk of atherosclerosis. HDL) are therefore devoid of this 2 The alterations generated in the Apoe apolipoprotein. As a result, Apoe Targeted Targeted Mutation Mice confer a Mutation Mice show dramatic alterations in lipid spontaneous susceptibility to early and metabolism and transport, even on a normal extensive development of atheromas mouse chow diet. regardless of diet. Unlike normal mice, which In normal mice, the protein apoE is made do not develop atherosclerotic lesions (except predominantly by the liver (as in humans) for some strains on high fat/high cholesterol and becomes incorporated into all lipoprotein diets), Apoe Targeted Mutation Mice fed normal particles (except LDL), including those mouse chow develop foam cell accumulations constructed by intestinal cells (chylomicrons) on their aortic walls by 3 months of age, which progress to extensive atherosclerotic lesions and for transport of ingested lipids through the 2 bloodstream, and those constructed by liver cells severe vessel occlusion by 8 months. to distribute lipids via the circulation and fuel 3 Other than lipid alterations and propensity to cellular metabolism during fasting (VLDLs). develop atherosclerosis, Apoe Targeted apoE is present in other lipoprotein particles that Mutation Mice are of similar weight to are metabolic products (IDLs, chylomicron normal mice and appear otherwise healthy.2 remnants), or those involved in acquisition of This, combined with early atherosclerosis and cholesterol from tissues and reverse cholesterol underlying changes in plasma lipid profile that transport (HDLs). mimic the human atherogenic profile, make The most well-documented function of apoE Apoe Targeted Mutation Mice an ideal model is to facilitate binding of lipoproteins to cell for human atherogenesis. They also can serve as surface receptors, thereby enhancing transfer of a model for human apoE deficiency, a rare components of the particle’s lipid moeity (e.g., genetic disorder. cholesteryl esters, triacyl-glycerols) to or from The apoE deficiency has been corrected cells. Specifically, apoE mediates binding to experimentally in Apoe Targeted Mutation both LDL and LRP (LDL receptor-related Mice, with a return to normal lipoprotein protein) receptors, and possibly the VLDL 4 distribution and cholesterol levels (650 mg/dl in receptor. Less well understood but intriguing apoE deficient mice versus 100-150 mg/dl in are possible roles for apoE in nerve regeneration apoE corrected mice).4 This was accomplished and amyloid processing in CNS neurons. by gene replacement through infusion of an 2 adenovirus vector containing the human Apoe Pathogen Free (MPFTM) health status. Barrier gene, and resulted in mice with markedly housing conditions are recommended for reduced incidence of atherosclerosis. maintenance of Apoe Targeted Mutation homozygous mice. Origin of the Model Related Mouse Models from Taconic The Apoe Targeted Mutation Mouse Model was developed by Nobuyo Maeda and colleagues at Taconic provides a number of mouse models the University of North Carolina in Chapel Hill.1 relevant to lipoprotein metabolism and Inactivation of the Apoe gene was accomplished atherogenesis. Call, fax, or visit Taconic’s by homologous recombination, by website for information about these additional electroporation of cultured E14TG2a cells with a models: plasmid that contains a modification of the • ApoB100 Microinjected Mouse (model murine Apoe locus, in which a portion of the 001004) – develops atherosclerosis on a normal Apoe gene sequence had been replaced high fat/high cholesterol diet, due to by neomycin-resistance and thymidine kinase expression of high levels of human marker genes. apolipoprotein B100 and a resultant elevated plasma cholesterol (total and LDL- Electroporated cells that had undergone associated). successful recombination of wild-type and • APOE2 Targeted Replacement Mouse plasmid-derived Apoe gene sequences were (model 001547) – expressing the human identified by positive neomycin resistance, and apoE2 protein instead of murine apoE, with hence, presence of the disrupted Apoe gene. several abnormalities of lipid physiology, Chimeric mice then were generated by injecting including elevated serum levels, altered such cells into blastocysts of C57BL/6J mice. lipoprotein profiles, and early development of atherosclerosis, all of which parallel Of the mice that developed from the blastocysts, features of human type III lipoproteinemia. a male chimera (JH126.1) was found to transmit • APOE3 Targeted Replacement Mouse the embryonic cell genome to 100% of his (model 001548) – expressing the human offspring in a backcross to a C57BL/6 female. apoE3 protein instead of murine apoE, with The resulting pups inherited the Apoe gene in normal serum cholesterol and triglyceride expected Mendelian proportion (50%), levels, but certain abnormalities of lipid indicating integration of the mutation into the physiology, including delayed clearance of genome and no effect of the mutation on embryo lipoprotein particles (VLDL) and propensity viability. to develop atherosclerosis on a high-fat diet. • APOE4 Targeted Replacement Mouse The mice were transferred to Taconic in May (model 001549) – expressing the human 1998 after ten backcrosses (N10) to C57BL/6J apoE4 protein instead of murine apoE, with from the (129 X C57BL/6) chimera and normal serum cholesterol and triglyceride intracrossing to homozygosity. The line was levels but certain abnormalities of lipid then further backcrossed at Taconic to physiology that are similar to those of C57BL/6N (N11) and derived by embryo ApoE3 Targeted Replacement Mice; transfer. The colony is maintained at N11 impairment in clearance of lipoprotein through intercrossing of homozygous mice. particles (VLDL) and development of atherosclerosis on a high-fat diet are more Ready for Your Experiments pronounced. Taconic’s Apoe targeted mutation mice are • CETP Microinjected Mouse (model produced
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