This Bin1 intron 1 SNP/hAbeta/APOE4/Trem2*R47H quadruple 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 allele of the App gene containing G601R, F606Y and R609H point mutations, a knock-in of a point mutation into mouse Trem2 gene containing an R47H point mutation with two silent mutations and a mutant allele of the Bin1 gene with a C-to-A point mutation in the promoter flanking region (between exon 1 and exon 2) that models human SNP rs10194375. 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. The targeted Bin1 gene encodes a nucleocytoplasmic adaptor protein that is able to act as a tumor suppressor when interacting with MYC and is involved in synaptic vesicle endocytosis and apoptosis. Mutations of the BIN1 gene are associated with centronuclear myopathy. Mice that are homozygous for Apoetm1.1(APOE*4)Adiuj (APOE4), Appem1Adiuj (hAbeta), Trem2em1Adiuj (Trem2*R47H) and Bin1em1Adiuj (Bin1 intron 1 SNP) are viable and fertile [March 2020]. If additional characterization of these Bin1 intron 1 SNP/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>).

Bin1 intron 1 SNP/hAbeta/APOE4/Trem2*R47H mice carry a CRISPR/cas9-generated C&gt;A mutation in intron 1 of the bridging integrator 1 locus. This models the Alzheimer's disease non-coding risk variant rs10194375. 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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