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 rs3752246 SNP knock-in mutation into the Abca7 gene (alanine to glycine at position 1527 in exon 33); 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 Abca7 gene encodes an ATP-binding cassette (ABC) transporter protein that moves lipids across membranes. Mutations in this gene have been associated with susceptibility to Alzheimer's disease. 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, Abca7em2Adiuj and Trem2em1Adiuj alleles are viable and fertile. 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 rs3752246 SNP knock-in mutation of the Abca7 gene (alanine to glycine at position 1527 in exon 33) 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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