B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax

Stock number: 006554
Product name: 5XFAD
Strain synonyms: Tg6799
Research areas: Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

These 5XFAD transgenic mice overexpress 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 along with human presenilin 1 (PS1) harboring two FAD mutations, M146L and L286V. Both transgenes are regulated by the mouse Thy1 promoter to drive overexpression in the brain. 5XFAD mice recapitulate major features of Alzheimer's Disease amyloid pathology and may be a useful model of intraneuronal Abeta-42 induced neurodegeneration and amyloid plaque formation.

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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 presenilin 1 (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 this 6799 founder line have high APP expression correlating with high burden and accelerated accumulation of the 42 amino acid species of beta-amyloid (Abeta-42). 5XFAD mice generate Abeta-42 almost exclusively, rapidly accumulating massive cerebral levels. On this mixed C57BL/6 and SJL background (MMRRC stock 34840), 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. On a congenic C57BL/6J genetic background (see MMRRC stock 34848) it has been the observation of the MMRRC that this phenotype in hemizygotes 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 (formally Cdk5) levels, neuron loss, reduced anxiety, poor novel object recognition, impaired conditioned behavior and memory impairment in the Y-maze test. 5XFAD males exhibit increased home cage aggression and decreased social investigation in both males and females. 5XFAD transgenic mice recapitulate major features of Alzheimer's Disease amyloid pathology and may be useful models of intraneuronal Abeta-42 induced neurodegeneration and amyloid plaque formation. Hemizygous mice are viable and fertile.

This strain is segregating heterozygous/wild-type for the retinal degeneration allele Pde6b^rd1.

It should be noted that the SJL genetic background contains the Trem2^S148E allele - a naturally occurring variant at position 48351151-48351152 on Chr 17 (rs108080490 and rs107649577; Ensembl GRCm38.p6). This TC to GA transition results in a serine to glutamic acid substitution at amino acid 148 (S148E). Because this model (MMRRC stock 34840) is maintained by backcrossing transgenic animals to a B6SJLF1 hybrid at every generation, SJL content is segregating in the progeny of these animals. Mice produced from this cross could be genotypically heterozygous, homozygous or wild-type for this Trem2^S148E. This variant may be of particular interest to those studying the role played by TREM2 (triggering receptor expressed on myeloid cells 2) in Alzheimer's Disease pathology.

NOTE: This 5XFAD transgene is also available on a C57BL/6J background (see MMRRC stock 34848), which does not carry the Trem2^S148E allele.

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. Of note, the APP transgene includes the 5' untranslated region and thus contains a putative interleukin-1beta translational enhancer element.

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
Marker symbol: Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas
Marker name: transgene insertion 6799, Robert Vassar
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.