B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax

Stock number: 008730
Product name: 5xFAD , 5x-FAD, Tg6799

Strain synonyms: 5XFAD
Research areas: Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

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5XFAD transgenic mice overexpress both mutant human amyloid beta (A4) precursor protein 695 (APP)) with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) Familial Alzheimer's Disease (FAD) mutations and human PS1 harboring two FAD mutations, M146L and L286V. Expression of both transgenes is regulated by neural-specific elements of the mouse Thy1 promoter to drive overexpression in the brain. These 5XFAD transgenic mice rapidly recapitulate major features of Alzheimer's Disease amyloid pathology and may be useful models of intraneuronal Aβ-42 induced neurodegeneration and amyloid plaque formation.

Detailed description

These 5XFAD transgenic mice overexpress both mutant human amyloid beta (A4) precursor protein 695 (APP) with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) Familial Alzheimer's Disease (FAD) mutations and human PS1 harboring two FAD mutations, M146L and L286V. Expression of both transgenes is regulated by neural-specific elements of the mouse Thy1 promoter to drive overexpression in the brain. Mice from the 6799 founder line have high APP expression correlating with high burden and accelerated accumulation of the 42 amino acid species of beta-amyloid (Aβ-42). 5XFAD mice generate Aβ-42 almost exclusively and rapidly accumulate massive cerebral levels. On a congenic C57BL/6J genetic background (this strain) it has been the observation of the MMRRC that this phenotype in hemizygous mice is not as robust as that demonstrated in hemizygotes from the mixed C57BL/6 and SJL background (view data). In addition, these mice have reduced synaptic marker protein levels, increased p25 levels, neuron loss, and memory impairment in the Y-maze test. On the mixed C57BL/6 and SJL background (see MMRRC datasheet RRID:MMRRC_034840-JAX), intraneuronal Abeta;-42 accumulation is observed starting at 1.5 months of age in hemizygotes, just prior to amyloid deposition and gliosis, which begins at two months of age. 5XFAD transgenic mice rapidly recapitulate major features of Alzheimer's Disease amyloid pathology and may be useful models of intraneuronal Aβ-42 induced neurodegeneration and amyloid plaque formation.

This strain does not carry the retinal degeneration allele Pde6b^rd1.

Parental origin of the 5xFAD transgene can affect plaque deposition:
Sasmita et al., 2025 Neuron [PMID:39837326] describes breeding C57BL/6 5xFAD hemizygous mice to wildtype (noncarrier) mice that they found paternal inheritance of the transgene (n=20 hemizygous offspring) led to a 2-fold higher plaque burden compared with maternal inheritance (n=11 hemizygous offspring) via quantitative light-sheet microscopy. Importantly, the extent of the observed effect is comparable with the known sex dimorphism of the 5xFAD model. This effect was not due to gestation-in or rearing-by 5xFAD females. Immunoblotting suggested that transgenic inheritance modulates transgenic protein expression, potentially due to genomic imprinting of a CpG island within the Thy1.2 promoter. Taken together, these findings underscore the importance of the AD research community to [1] systematically report breeding schemes in publications, [2] ensure the comparison of inheritance-matched cohorts, and [3] critically review past publications for inheritance mismatches as a confounding variable.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for Stock No. 008730. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

A transgene was designed with a mutant human amyloid beta (A4) precursor protein (APP) cDNA sequence (altered to include the APP K670N/M671L (Swedish) + I716V (Florida) + V717I (London) Familial Alzheimer's Disease (FAD) mutations) inserted into exon 2 of the mouse Thy1 gene. A second transgene was designed with a mutant human presenilin 1 (Alzheimer disease 3) (PSEN1 or PS1) cDNA sequence (altered to include the PS1 M146L + L286V FAD mutations) inserted into exon 2 of the mouse Thy1 gene. Both transgenes were added together in equal proportions and co-injected into the pronuclei of single-cell "C57BL/6XSJL" hybrid embryos. Founders from the highest APP expressing line (Tg6799) were bred with (B6SJL)F1 mice for more than 10 generations with stable germ-line transmission and expression of both transgenes, demonstrating that these "5XFAD" mice breed as single transgenics. The mice were then backcrossed to C57BL/6J mice using a speed congenic protocol and the retinal degeneration allele Pde6b^rd1 was bred out of the strain. Of note, the APP transgene includes the 5' untranslated region and thus contains a putative interleukin-1beta translational enhancer element.

The 5xFAD transgenes are reported to have co-inserted onto Chromosome 3 ~63 Mb [MGI:3693208].

Allele

Symbol: Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas
Name: transgene insertion 6799, Robert Vassar
MGI accession ID: MGI:3693208
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: 5XFAD; 5XFAD APP/PS1; 5XFAD line Tg6799; Tg(APP*Swe*Fl*Lon,PSEN1*M146L*L286V)6799Vas; Tg-5xFAD; Tg6799
Marker symbol: Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas
Marker name: transgene insertion 6799, Robert Vassar
Marker synonyms: 5XFAD; 5XFAD line Tg6799; Tg6799
Chromosome: 3
Strain of origin: (C57BL/6 x SJL)F1
Expressed genes: PSEN1,presenilin 1,human; APP695,amyloid beta (A4) precursor protein (chimeric),mouse/human chimera
Site of expression: Expression is directed to the brain by neural-specific elements of the mouse Thy1 promoter

Molecular note: Four familial Alzheimer disease- (FAD-) associated mutations were introduced into a single human amyloid precursor protein cDNA: the "Swedish" double mutation (K670N/M671L); the "Florida" mutation (I716V); and the "London" mutation (V717I). Two FAD-associated mutations, M146L and L286V, likewise were introduced into a human presenilin 1 cDNA. Each cDNA was then cloned independently into the mouse thymus cell antigen 1 gene, replacing a segment that contains thymus-specific elements so that expression of the transgenes is targeted only to the brain. Equal molar amounts of the two transgenes were coinjected into pronuclei of single-celled embryos.
General note: Three transgenic lines coexpressing the APP and PSEN1 proteins at high, medium and low levels, respectively designated Tg6799, Tg7031, and Tg7092, were propagated for analysis, most of which employed Tg6799.

Phenotypic Similarity to Human Syndrome: Macular Degeneration, Age-Related J:214858.