This triple mutant strain carries a humanized ApoE knock-in allele, in which exons 2, 3 and most of exon 4 of the mouse Apoe gene were replaced by human APOE4 gene sequence including exons 2, 3 and 4 (and some 3' UTR sequence); a mutant knock-out allele, 387bp deletion in the first coding exon, of the Il1rap gene; and a knock-in of a point mutation into mouse Trem2, triggering receptor expressed on myeloid cells 2, gene containing a R47H point mutation, with two silent mutations. The targeted Apoe gene encodes apolipoprotein E, which is important in lipoprotein metabolism and cardiovascular disease as well as Alzheimer's disease, immunoregulation and cognition. The targeted Il1rap gene encodes interleukin 1 receptor accessory protein which is a component of the interleukin 1 receptor complex, and is involved in interleukin 1 signalling. The targeted Trem2 gene encodes a protein that is part of a receptor signaling complex with TYRO protein tyrosine kinase binding protein, and that activates macrophages and dendritic cells during immune responses. The TREM2 R47H mutation is a missense mutation in exon 2 that is one of the strongest genetic risk factors for late-onset Alzheimer's disease. Mice that are homozygous for the Apoetm1.1(APOE*4)Adiuj and Trem2em1Adiuj alleles, and heterozygous for the Il1rapem1Adiuj allele are viable and fertile. Homozygous viability/fertility has not been tested for the Il1rapem1Adiuj allele (June 2018). As the mice are characterized, we will modify the strain description and add phenotype data. Of note, in brains of mice homozygous for the Trem2em1Adiuj allele (and not carrying any other mutant alleles), expression of both transcripts of Trem2 is decreased by about 50%. Mice expressing the Trem2 R47H mutation also express a novel splice variant with a deletion of 119bp at the 5&rsquo; end of exon 2, due to a cryptic splice acceptor site in exon 2 (see Stock No. <a href="https://www.jax.org/strain/027918">027918</a>).

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This triple mutant strain carries a humanized ApoE knock-in mutation (sequence coding for isoform E4), a CRISPR/Cas9-generated 387bp deletion in the first coding exon knock-out mutation of the Il1rap gene and a CRISPR/cas9-generated R47H point mutation of the Trem2 gene. These mice may be suitable for use in studies related to Alzheimer's disease, lipoproteins, arteriosclerosis, and coronary heart disease.

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