Il1rapex3KO/hAbeta/APOE4/Trem2*R47H quadruple mutant strain carries a mutant allele of the Il1rap lacking exon 3 (modeling human intronic variant rs12053868), 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 allele of the App gene containing G601R, F606Y and R609H point mutations and a knock-in of a point mutation into mouse Trem2 gene containing an R47H point mutation with two silent mutations. The targeted Il1rap gene encodes a component of the interleukin 1 receptor complex, which initiates signaling events that result in the activation of interleukin 1-responsive genes. The encoded gene has also been associated with amyloid accumulation in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. 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 App gene encodes amyloid beta precursor protein, a transmembrane cell surface receptor that is cleaved by secretases. Mutations in this gene have been associated with Alzheimer's disease. The targeted Trem2 gene (triggering receptor expressed on myeloid cells 2) 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 Il1rapem2Adiuj (Il1rapex3KO), Apoetm1.1(APOE*4)Adiuj (APOE4), Appem1Adiuj (hAbeta) and Trem2em1Adiuj (Trem2*R47H) are viable and fertile [June 2021]. If additional characterization of these Il1rapex3KO/hAbeta/APOE4/Trem2*R47H mice is performed, we may modify the strain description accordingly. 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' 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 model has a CRISPR/cas9-generated deletion of exon 3 of the Il1rap (interleukin 1 receptor accessory protein) gene. The IL1RAP intronic variant rs12053868 is associated with amyloid accumulation in the ADNI cohort. This mutation is maintained with the hAbeta/APOE4/Trem2*R47H mutations (Stock No. <a href="https://www.jax.org/strain/030670">030670</a>) intended to increase risk of late-onset Alzheimer's disease: a humanized Apoe knock-in mutation (sequence coding for human isoform E4), a CRISPR/Cas9-generated App allele with a humanized Abeta1-42 region (G601R, F606Y, R609H in the mouse gene, corresponding to amino acid positions 676, 681, 684 in the human APP locus) and a CRISPR/Cas9-generated R47H point mutation of the Trem2 gene.

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