Mutations: APP KM670/671NL, APP V717I (London)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: 129S6FVB F1
Availability: Available through Karen Ashe
This is a regulatable transgenic model of AD that expresses mutant human APP preferentially in excitatory neurons of the forebrain. Human APP protein is expressed at levels fourfold higher than the endogenous mouse protein in the brain (Liu et al., 2015). In addition to overexpressing APP, the particular mutations expressed in this transgenic stimulate higher overall levels of Aβ production (Swedish mutation), as well as shift APP processing toward Aβ42 (London mutation). The mice develop age-associated amyloid pathology in the cerebral cortex and hippocampus along with specifically fibrillar Aβ oligomers. They also develop hyperphosphorylated tau and neuroinflammation, but cognitive performance appears intact even at advanced age.
Plaques emerge first in the cerebral cortex, starting around 8 months of age. This is followed by plaques in the hippocampus at 10½ to 12½ months of age. Plaque deposition increases with age in both regions, ultimately occupying 17 to 19 percent of the parenchyma at 25 months of age. This is considered a moderate plaque load, comparable to levels seen in the AD brain, and contrasts with other well-known models (e.g. 5xFAD and APPswe/PSEN1dE9), which typically develop much greater amyloid burdens. A small percentage of plaques were of the dense-core variety, and these were frequently surrounded by reactive astrocytes and microglia.
In addition to plaques, oligomeric Aβ species were detected in these mice, specifically fibrillar (OC-immunoreactive) oligomers. These oligomers were produced in an age-dependent manner, and included species that appear as Aβ dimers in western blots, under denaturing conditions. Dimers were not detectable at 12 months, but increased steeply from 21 to 24 months of age. Non-fibrillar oligomeric species, such as Aβ*56, were not detectable at any age, suggesting that the rTg9191 model may be useful for investigating the specific contribution of fibrillar Aβ oligomers.
Despite accumulating hippocampal and cortical amyloid pathology and fibrillar oligomers, behavioral tests indicate that these mice are cognitively intact even at advanced ages (e.g. 21–24 months). At 23 months of age, the mice performed similarly to littermates without the APP transgene in the fixed consecutive-number task, which is dependent on the frontal cortex. Likewise, spatial memory was intact at 4, 12, 21, and 24 months of age, as assessed by the Morris water maze, which is sensitive to hippocampal pathology (Liu et al., 2015).
A caveat to this model, as well as others that use the tTA activator, is that tTA expression produced brain changes independent of transgene expression. Mice expressing tTa (rTg9191, as well as those expressing tTA alone) had lower forebrain weights and smaller dentate gyri than littermates not expressing tTA. This effect was observed across the lifespan, suggesting that tTA expression affects brain development (Liu et al., 2015).
The data on this page refer to hemizygous mice.
These are bigenic mice using the CAMKII-α promoter to drive expression of a tetracycline transactivator (tTA) in excitatory neurons in the forebrain, and a responder transgene consisting of mutant human APP (isoform 695) carrying the Swedish and London mutations. Transgene expression is constitutive until suppressed by doxycycline.
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 rTg919 phenotype awaits further study.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cognitive Impairment
- Synaptic Loss
- Changes in LTP/LTD
Plaques emerge first in the cerebral cortex, starting around 8 months of age. This is followed by plaques in the hippocampus at 10.5 to 12.5 months of age. Some dense core plaques develop.
Tangles are not observed, but hyperphosphorylated tau develops with age.
Expression of the tetracycline transactivator (tTA) resulted in reduced forebrain weight and smaller dentate gyri in rTg9191 mice compared to non-Tg littermates. This effect was also observed in mice expressing tTA alone, and is thought to be a developmental effect, as it was observed even in young mice (e.g., 2-6 months of age).
rTg9191 mice develop reactive gliosis (astrocytosis and microgliosis) in the vicinity of dense-core plaques by 24 months of age.
Changes in LTP/LTD
No transgene-related deficits seen in Morris water maze (4, 12, 21, 24 months of age) or fixed consecutive number test (23 months of age).
Last Updated: 13 Apr 2018
Research Models Citations
- Liu P, Paulson JB, Forster CL, Shapiro SL, Ashe KH, Zahs KR. Characterization of a Novel Mouse Model of Alzheimer's Disease--Amyloid Pathology and Unique β-Amyloid Oligomer Profile. PLoS One. 2015;10(5):e0126317. Epub 2015 May 6 PubMed.
- Liu P, Reed MN, Kotilinek LA, Grant MK, Forster CL, Qiang W, Shapiro SL, Reichl JH, Chiang AC, Jankowsky JL, Wilmot CM, Cleary JP, Zahs KR, Ashe KH. Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration. Cell Rep. 2015 Jun 23;11(11):1760-71. Epub 2015 Jun 4 PubMed.
- 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