APOE-KO Mouse Model

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Strain Name	C57BL/6NMcl- Apoe<sup>tm1(KO)</sup>/MCL
Strain Background	C57BL/6N
Catalog No.	M10021
Gene Full Name	Apolipoprotein E
Gene Synonyms	Apo-E
NCBI	Gene ID: 11816 / MGI: 88057
Microbial grade	SPF

1. Research on the mechanisms of hyperlipidemia and lipid metabolism disorders
2. Research on the occurrence and progression of atherosclerosis
3. Research on cardiovascular inflammation and plaque formation mechanisms
4. Research on the efficacy evaluation of lipid-lowering, anti-inflammatory and anti-atherosclerotic drugs

Apoe-KO mice are generated via gene editing by deleting the entire coding region of the Apoe gene in C57BL/6N mice. In this model, endogenous murine ApoE protein expression is abolished, establishing a stable phenotype characterized by dysregulated lipoprotein metabolism and susceptibility to atherosclerosis.

Atherosclerotic cardiovascular disease is a chronic disorder driven collectively by lipid deposition, vascular wall inflammation, and fibrous proliferation. Cumulative evidence from genetics, epidemiology and randomized clinical trials demonstrates a definitive causal relationship between sustained circulating levels of low-density lipoproteins and other apolipoprotein B-containing lipoproteins and atherosclerotic cardiovascular events[1]. Currently, statins, cholesterol absorption inhibitors, PCSK9 inhibitors and other lipid-lowering agents are the mainstay of clinical risk management. Nevertheless, many patients still experience insufficient lipid control, residual cardiovascular risk, variable therapeutic responses, and burdens associated with long-term medication. In recent years, drug discovery in this field has expanded beyond conventional small-molecule lipid-lowering compounds to encompass monoclonal antibodies, nucleic acid therapeutics, and candidate agents targeting vascular inflammation and plaque stability. Accordingly, there is an urgent demand for well-characterized preclinical in vivo models that exhibit persistent hyperlipidemia, reproducible plaque formation, and clearly defined pathological readouts.

The APOE gene encodes apolipoprotein E, a secreted apolipoprotein involved in lipoprotein trafficking and cholesterol homeostasis. Circulating ApoE is predominantly synthesized in the liver, with additional expression in macrophages, astrocytes and other cell types. ApoE resides on the surface of chylomicron remnants, very-low-density lipoproteins, intermediate-density lipoproteins and a subset of high-density lipoprotein particles. Acting as a ligand for the low-density lipoprotein receptor and related receptor families, it facilitates hepatic uptake and clearance of triglyceride-rich lipoprotein remnants[2]. Beyond systemic clearance of circulating lipoproteins, macrophage-derived ApoE participates in cholesterol efflux, foam cell biogenesis, and local modulation of vascular wall inflammation. Loss of ApoE function therefore simultaneously impairs the removal of remnant lipoproteins in circulation and disrupts arterial lipid homeostasis, promoting hypercholesterolemia and the initiation of atherosclerosis.

Classical studies have confirmed that Apoe-deficient mice develop marked hypercholesterolemia on standard chow diets and spontaneously form atherosclerotic lesions at the aortic root, aortic arch and other arterial segments[3,4]. Upon Apoe deletion, clearance of cholesterol-laden chylomicron remnants and VLDL remnants is blocked, leading to persistent accumulation of remnant lipoproteins in the circulation. After infiltrating the vascular intima, these lipoproteins are taken up by macrophages, driving foam cell formation. Progressive lipid deposition, monocyte recruitment and inflammatory responses enable lesions to advance from early fatty streaks to complex plaques consisting of macrophages, smooth muscle cells, collagen and necrotic cores. High-fat or Western-type diets further accelerate lesion progression. Moreover, Apoe^-/- mice can be crossed with other gene-edited strains to investigate lipid metabolism, immune inflammation, oxidative stress, endothelial function, and mechanisms governing plaque progression and regression[5]. It should be noted that this model recapitulates hyperlipidemia and atherosclerosis resulting from complete ApoE ablation, and cannot substitute humanized APOE2, APOE3 or APOE4 knock-in models for subtype-specific functional research.

A multi-tiered therapeutic intervention landscape has emerged for atherosclerosis drug development. Conventional small molecules lower circulating atherogenic lipoproteins by inhibiting cholesterol biosynthesis or intestinal cholesterol absorption. PCSK9 monoclonal antibodies disrupt the interaction between PCSK9 and the LDL receptor, reducing receptor degradation and enhancing hepatic LDL clearance; clinical trials have validated their capacity to substantially lower LDL-cholesterol and mitigate cardiovascular events[6]. siRNA therapeutics such as inclisiran suppress hepatic PCSK9 synthesis via RNA interference to achieve durable LDL-cholesterol reduction[7]. In addition, candidate agents targeting lipoprotein production and clearance, cholesterol efflux, monocyte recruitment, foam cell formation and vascular inflammation require in vivo validation in animal models with consistent plaque phenotypes.

The established APOE-KO mouse model enables the evaluation of lipid-lowering small molecules, lipoprotein metabolism modulators, anti-inflammatory drugs, antioxidants, nucleic acid therapeutics and other anti-atherosclerotic candidate interventions. Key measurable endpoints supported by this model include plasma total cholesterol, non-HDL cholesterol and remnant lipoprotein concentrations, as well as total aortic plaque burden, aortic root lesion area, plaque macrophage infiltration, collagen content and necrotic core size. For antibodies and nucleic acid agents that exclusively recognize human proteins or human nucleic acid sequences, further humanization of relevant target genes can be performed on the APOE-KO background. This model is applicable to in vivo pharmacodynamic assessment, candidate drug screening, mechanistic investigation, dose optimization, dietary intervention studies, combination therapy evaluation and preclinical translational research. It provides a stable, reproducible in vivo evaluation platform supporting the development of therapeutics for hyperlipidemia and atherosclerosis.

References

[1] Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. doi: 10.1093/eurheartj/ehx144. PMID: 28444290.

[2] Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240(4852):622-630. doi: 10.1126/science.3283935. PMID: 3283935.

[3] Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992;71(2):343-353. doi: 10.1016/0092-8674(92)90362-G. PMID: 1423598.

[4] Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992;258(5081):468-471. doi: 10.1126/science.1411543. PMID: 1411543.

[5] Getz GS, Reardon CA. ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis. J Lipid Res. 2016;57(5):758-766. doi: 10.1194/jlr.R067249. PMID: 27015743.

[6] Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. PMID: 28304224.

[7] Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. PMID: 32187462.

1. Achieve Apoe gene knockout
By destroying the endogenous Apoe gene in mice and deleting APOE protein expression, the functional defective state of apolipoprotein E can be stably simulated.
2. Formation of typical hyperlipidemia and atherosclerosis phenotypes
APOE deficiency leads to impaired lipoprotein clearance, elevated plasma cholesterol levels, and the formation of significant atherosclerotic lesions under appropriate feeding conditions.
3. Suitable for evaluation of cardiovascular and metabolic drugs
It can be used to study the in vivo efficacy, mechanism of action and safety of lipid-lowering drugs, anti-inflammatory drugs, anti-atherosclerotic drugs and gene therapy drugs.

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How much for a project assessment?

•Free initial design proposal with zero obligations.
•Request a free quote!

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APOE-KO Mouse Model

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APOE-KO Mouse Model

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