B6(Cg)-Apoe^{tm1.1(APOE*4)Adiuj} Isr(HSA17)1Mdk App^tm1.1Aduci/AduciJ

Stock number: 038104
Product name: MAD1
Strain synonyms: B6(Cg)-Apoe^{tm1.1(APOE*4)Adiuj} Tc(HSA17)1Mdk App^tm1.1Aduci/AduciJ
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

MODEL-AD 1 (MAD1) mice are a triple mutant line generated by crossing APOE4 KI mice (Stock No. 027894), hAbeta-loxP-KI mice (Stock No. 031050), and MAPT(H2.1)-GR mice (Stock No. 033668). They are useful when studying late-onset Alzheimer's disease.

Detailed description

MODEL-AD 1 (MAD1) mice are a triple mutant line generated by crossing APOE4 KI mice (Stock No. 027894), hAbeta-loxP-KI mice (Stock No. 031050), and MAPT(H2.1)-GR mice (Stock No. 033668).

MAD1 mice carry an App allele with a floxed humanized Abeta1-42 region (G601R, F606Y, R609H in the mouse gene, corresponding to amino acid positions 676, 681, 684 in human APP), a humanized ApoE knock-in mutation (sequence coding for isoform E4), and the human MAPT (H2.1 haplotype), MAPT-AS1 transcripts and the typical MAPT protein isoforms, including SPPL2C. Additional information on each allele may be obtained from the respective stock number entry.

MAD1 mice may be suitable for use as a platform strain to test genetic and environmental factors that predispose to the development of characteristics associated with late-onset Alzheimer's disease, as MAD1 mice express humanized non-pathogenic alleles believed to be necessary, but not sufficient for development of late-onset Alzheimer's disease.

Important note about App isoforms and exon numbering: The App-201 isoform (695 aa protein) is encoded by 16 exons, of which the Abeta sequence is encoded by exon 14. The App-206 isoform (770 aa protein) is encoded by 18 exons, of which the Abeta sequence is encoded by exon 16.

Development

This triple mutant line was generated by crossing B6(SJL)-Apoe^{tm1.1(APOE*4)Adiuj} mice (Stock No. 027894), B6(Cg)-App^tm1.1Aduci/J mice (Stock No. 031050), and B6J.B6N(CBA)-Tc(HSA17)1Mdk/J (Stock No. 033668) mice. Resulting MAD1 mice were maintained as a triple homozygous colony on a congenic C57BL/6J background (see SNP note below).



In 2025, a 48 SNP (single nucleotide polymorphism) panel analysis, with 43 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. One of the markers that determine C57BL/6J from C57BL/6N was found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.

Allele

Symbol: App^tm1.1Aduci
Name: targeted mutation 1.1, Frank LaFerla
MGI accession ID: MGI:6120494
Generation method: Targeted
Attributes: Conditional ready (e.g. floxed); Humanized sequence
Synonyms: hABeta-KI
Marker symbol: App
Marker name: amyloid beta (A4) precursor protein
Marker synonyms: AAA; Abeta; ABPP; AD1; Adap; alpha-sAPP; APPI; appican; betaAPP; CTFgamma; Cvap; E030013M08Rik; PN2; PN-II; preA4; protease nexin II
Chromosome: 16
Strain of origin: C57BL/6N
Molecular note: The targeting construct includes a loxP site upstream of exon 16 of App-206 isoform, 3 point mutations inserted into exon 14 to create amino acid substitutions (amino acids 5 (G->R), 10 (F->Y) and 13 (R->H)) (ENSMUSE00000131684), a loxP site downstream of exon 16 and a FRT-flanked neo selection cassette, which is removed by FLP-mediated recombination.

Allele

Symbol: Apoe^{tm1.1(APOE*4)Adiuj}
Name: targeted mutation 1.1, MODEL-AD Center
MGI accession ID: MGI:5810209
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: APOE^epsilon4
Marker symbol: Apoe
Marker name: apolipoprotein E
Marker synonyms: AD2; APO-E; ApoE4; APOEA; LDLCQ5; LPG
Chromosome: 7
Strain of origin: C57BL/6J
Expressed genes: APOE,apolipoprotein E,human
Site of expression: Endogenous mouse elements direct human APOE gene sequence (including exons 2, 3 and 4 and some 3' UTR sequence).
Molecular note: The targeting vector contains a 3' FRT flanked neo cassette and 1.5 kb of human APOE gene sequence including exons 2, 3, 4 and a portion of the 3'UTR sequence (the APOE4 isoform) which is used to replace exons 2, 3 and most of exon 4 of the endogenous sequence. The human APOE sequence carries a 2 nucleotide A-to-T substitution in intron 3. Flp-mediated recombination removed the FRT-flanked neo cassette.

Allele

Symbol: Isr(HSA17)1Mdk
Name: interspecies replacement, human Chr 17, Michael Koob 1
MGI accession ID: MGI:6363617
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: MAPT-GR; Tc(HSA17)1Mdk
Marker symbol: Isr(HSA17)1Mdk
Marker name: interspecies replacement, human Chr 17, Michael Koob 1
Marker synonyms: Tc(HSA17)1Mdk
Chromosome: 11
Strain of origin: C57BL/6NTac
Site of expression: neurons of the central nervous system and at low levels in astrocytes and oligodentrocytes

Molecular note: A 157 kb deletion on mouse Chromosome 11 stretching from, but not including, Crhr1 to Kansl1 is replaced by a syntenic 190 kb region from human Chromosome 17 (HSA17). In this interspecies replacement (Isr) strain, the mouse Sppl2c (signal peptide peptidase 2C) and Mapt (microtubule-associated protein tau) genes are replaced by human SPPL2C and MAPT genes and a loxN-flanked hygromycin cassette. Cre-mediated recombination removed the hygromycin cassette.