B6J.B6N-Isr(HSA19;APOE_i4)2Mdk/J

Stock number: 038919
Product name: APOE4-GR
Strain synonyms: B6J.B6N-Tc(HSA19*APOE_i4)1Mdk/J
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

Humanized transchromosomal APOE4-GR (gene replacement) mice are a knock-in/knock-out model in which the mouse genomic region from Apoe (apoliprotein E) to Apoc (apoliprotein C) is exchanged for the 47 kb human genomic region APOE to APOC which includes human APOEε4. These mice may serve as base models into which additional alterations can be introduced to explore more fully the complex cis-regulatory controls in the human 19q13.32 region associated with cardiovascular risk, altered levels of inflammatory markers, altered lipid metabolism, late onset Alzheimer's Disease (LOAD) risk and age-at-onset (AAO) risk.

Of note, the APOE3-GR strain is distributed as B6J.B6N-Tc(HSA19*APOE_i3)1Mdk/J (Stock No. 038918).

Detailed description

The human 19q13.32 region (APOE-APOC1) genomic region is associated with multiple phenotypes, including cardiovascular risk, altered levels of inflammatory markers, altered lipid metabolism, late-onset Alzheimer's Disease (LOAD) risk, and age-at-onset (AAO) risk. The humanized interspecies replacement (Isr) APOE4-GR (gene replacement) mice are a knock-in/knock-out model in which the mouse genomic region (Chr7:19,404,448-19,434,653; 3,0206bp) between but not including Tomm40 (translocase of outer mitochondrial membrane 40) to Clptm1 (cleft lip and palate associated transmembrane protein 1) are replaced by the human syntenic region containing APOE to APOC (including promoter, regulatory and intergenic regions, Chr19:44,904,076-44,951,132; 47,057bp), which includes the APOEε4 locus. The Apoc/APOC region includes Apoc1, Apoc4, Apoc2. APOEε4 differs from APOEε3 by an arginine (CGC) rather than cysteine (TGC) at SNP rs429358 (Ensembl, SNPedia). The APOE Ε4 (ApoE4) allele is the strongest genetic risk factor for developing late-onset Alzheimer's disease and also increases the risk of dementia with Lewy bodies. Homozygous mice are viable and fertile with no obvious anatomical or behavioral issues.

Of note, the APOE3-GR strain is distributed as B6J.B6N-Tc(HSA19*APOE_i3)1Mdk/J (Stock No. 038918).

Development

A 30 kb deletion on mouse chromosome 7 stretching from Apoe to Apoc is replaced by a syntenic 47 kb region from human chromosome 19 (HSA19). In this transchromosomal (Tc) strain, the mouse Apoe (apoliprotein e) isoform 4 and Apoc (apolipoprotein C) genes are replaced by human APOE (isoform E4) and APOC genes. A neomycin resistance cassette was included in the construct. The deletion/insertion was made using C57BL/6N-PRX-B6N embryonic stem cells (ES) and loxP-flanked neomycin resistance cassette was removed by transient expression of cre. Correctly targeted ES cells were injected into blastocysts. Mice were backcrossed to C57BL/6J mice (Stock No. 000664) for at least 5 generations by the donating laboratory. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes.

Allele

Symbol: Isr(HSA19;APOE_i4)2Mdk
Name: interspecies replacement, human Chr 19, Michael Koob 2
MGI accession ID: MGI:7565468
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: APOE4-GR; Tc(HSA19*APOE_i4)1Mdk
Marker symbol: Isr(HSA19;APOE_i4)2Mdk
Marker name: interspecies replacement, human Chr 19, Michael Koob 2
Marker synonyms: Tc(HSA19*APOE_i4)1Mdk
Chromosome: 7
Strain of origin: C57BL/6NTac
Molecular note: A 30 kb deletion on mouse chromosome 7 stretching from Apoe to Apoc is replaced by a syntenic 47 kb region from human chromosome 19 (HSA19). The mouse Apoe (apoliprotein e) isoform four and Apoc (apolipoprotein C) genes are replaced by human APOE (isoform E4) and APOC genes. A loxP-flanked neomycin resistance cassette is included in the construct. The neomycin cassette was removed by transient expression of Cre.