Species: Mouse
Genes: APP, PSEN1, MAPT
Mutations: APP K670_M671delinsNL (Swedish), PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: B6.C3 x B6.129 x FVB
Availability: APPswe/PSEN1dE9 mice available through JAX MMRRC Stock# 034829.

To investigate the influence of human tau (hTau) on amyloid pathology, APP^swe/PSEN1^dE9 (APP/PS1) mice were crossed with the CaMKIIa-tTA and Tg21221 lines to create the APP/PS1/rTg21221 mouse. The transgene from the Tg21221 mouse encodes wild-type hTau with four microtubule binding domains and lacking amino terminal inserts (4R/0N) under control of a tetracycline responsive elements (TRE) promotor (Hoover et al., 2010). While the APP^swe and PSEN1^dE9 transgenes are constitutively expressed from mouse prion promoters, this model also uses the TET-OFF system to allow for temporal control of hTau expression. The transcriptional transactivator (tTA) is driven by the CaMKIIα promoter, resulting in preferential forebrain expression of tTA, and thus of transgenic hTau. Although not utilized in these experiments, the TET-OFF system would allow for suppression of hTau expression with the addition of doxycycline (dox) to the diet. Mice of both genders were analyzed between eight and 10 months of age; other time points were not examined (Jackson et al., 2016).

Staining with Thioflavin-S and the AW7 antibody revealed that plaque burden, as measured by a percent of cortical area occupied by plaques, and the diameter of Aβ halos around dense plaques were not different between APP/PS1/rTg21221 mice and APP/PS1 controls. There was, however, an increase in size of Thioflavin-S plaques in APP/PS1/rTg21221 mice compared to APP/PS1 animals. By ELISA, Aβ42 levels were also elevated in brain lysates from APP/PS1/rTg21221 mice.

Brain regions near plaques (<30mm) had a small amount of neuronal loss, while areas further from plaques were unaffected. Astrocytosis was also observed near plaques. Neuron loss and astrocytosis phenotypes were both unaffected by presence of hTau in the APP/PS1/rTg21221 mice relative to control animals.

While neither genotype showed evidence of neurofibrillary tangles, APP/PS1/rTg21221 mice demonstrated an increase in dystrophic neurites with accumulations of phosphorylated tau near amyloid plaques. Additionally, both mouse lines exhibited neuropil threads, but they were increased in APP/PS1/rTg21221 mice.

To examine the effect of hTau on synapse loss, array tomography was used to analyze cortical synapses from APP/PS1/rTg21221 and APP/PS1 mice. Synapse density, as measured by synapsin-1 and PSD-95 puncta, was decreased adjacent to plaques but there were no differences between the genotypes. Aβ co-localization with synapses was much higher near plaques compared to more distal brain regions, while co-localization was not different between the two mouse lines.

Modification Details

The transgene in the APP/PS1 line inserted at Chr9:113003660 (Build GRCm38/mm10), causing a 1 bp duplication that does not affect any known genes (Goodwin et al., 2017). The CaMKIIα-tTA transgene inserted on chromosome 12, resulting in a 508 kb deletion that affects five mouse genes: Vipr2 (vasoactive intestinal peptide receptor 2), Wdr60 (WD repeat-containing protein 60), Esyt2 (extended synaptotagmin-like protein 2), Ncapg2 (non-SMC condensin II complex, subunit G2), and Ptprn2 (protein tyrosine phosphatase, receptor type, N polypeptide 2) (Goodwin et al., 2017). To what extent, if any, disruption of these mouse genes contributes to the development of the rTg21221 phenotype awaits further study.

Related Strains

APPswe/PSEN1dE9

Phenotype Characterization

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References

Paper Citations

1. Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed.
2. Jackson RJ, Rudinskiy N, Herrmann AG, Croft S, Kim JM, Petrova V, Ramos-Rodriguez JJ, Pitstick R, Wegmann S, Garcia-Alloza M, Carlson GA, Hyman BT, Spires-Jones TL. Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease. Eur J Neurosci. 2016 Dec;44(12):3056-3066. Epub 2016 Nov 12 PubMed.
3. Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. bioRχiv preprint first posted online Dec. 18, 2017

Other Citations

1. APPswe/PSEN1dE9

External Citations

1. JAX MMRRC Stock# 034829

Further Reading

No Available Further Reading