Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax
Genetic Background: (C57BL/6 x SJL)F1
Availability: The Jackson Lab; available through the JAX MMRRC Stock# 034840; Live
These widely-used mice recapitulate many AD-related phenotypes and have a relatively early and aggressive presentation. The Tg6799 line, which expresses high levels of mutant APP and PSEN1, was generated along with two other lines with medium (Tg7031), and low (Tg7092), expression levels. The Tg6799 line is now the most widely used of the three, and is also available on a congenic background (see below).
The 5xFAD model rapidly develops severe amyloid pathology. These mice accumulate high levels of intraneuronal Aβ42 around 1.5 months of age with amyloid deposition rapidly following around two months, first in the subiculum and layer 5 of the cortex and increasing rapidly with age. Plaques spread throughout the hippocampus and cortex by six months of age. Gliosis also begins around two months, developing in parallel with plaque deposition. Synapse degeneration is also observed (at approximately four months) as well as neuronal loss and deficits in spatial learning (at approximately four to five months) (Oakley et al., 2006). Tangles are not typical in this model. LTP is normal in young animals, but becomes impaired around six months (Kimura et al., 2009). Specifically, in hippocampal slices from mice younger than four months old, I/O curves of fEPSPs in response to different stimulation strengths were not different from those of wild-type controls; but the I/O responses at Schaffer collateral-CA1 synapses in 5XFAD mice at six months showed deficits when compared with those of their wild-type littermate controls.
This model was previously available at The Jackson Lab as Stock# 006554.
These transgenic mice were made by co-injecting two vectors encoding APP (with Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations) and PSEN1 (with M146L and L286V mutations), each driven by the mouse Thy1 promoter. The transgenes inserted at a single locus, Chr3:6297836 (Build GRCm38/mm10), where they do not affect any known genes (Goodwin et al., 2017).
The Jackson Lab; the JAX MMRRC Stock# 034848 (formerly Jackson Lab Stock# 008730)
This congenic strain was generated by backcrossing to C57BL/6J mice. The retinal degeneration allele Pde6brd1 was bred out of the original strain. The Jackson Lab has observed a less robust amyloid phenotype in congenic animals compared with those on a hybrid B6SJL background.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Amyloid deposition begins at 1.5 months and reaches high levels especially in subiculum and deep cortical layers. Aβ42 also accumulates intraneuronally in an aggregated form within the soma and neurites starting at 1.5 months (Oakley et al., 2006).
Neuron loss in cortical layer 5 and subiculum.
Gliosis begins at 2 months (Oakley et al., 2006).
Synaptic markers synaptophysin, syntaxin, and PSD-95 decrease with age and are significantly reduced by 9 and 12 months.
Changes in LTP/LTD
LTP is normal in young animals, but becomes impaired around 6 months (Kimura et al., 2009); specifically, in hippocampal slices from < 4-month-old mice, I/O curves of fEPSPs were not different from those of wild-type controls, but the I/O responses at Schaffer collateral-CA1 synapses at 6 months were impaired.
Impaired spatial memory in Y-maze test at 4-5 months. Impaired stress-related memory, specifically significantly lower levels of contextual freezing at 6 months. Impaired remote memory stabilization at < 4 months.
- Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006 Oct 4;26(40):10129-40. PubMed.
- Kimura R, Ohno M. Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis. 2009 Feb;33(2):229-35. Epub 2008 Nov 5 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. bioRxiv preprint first posted online Dec. 18, 2017
- Xu F, Kotarba AE, Ou-Yang MH, Fu Z, Davis J, Smith SO, Van Nostrand WE. Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice. J Biol Chem. 2014 Jun 20;289(25):17895-908. Epub 2014 May 14 PubMed.
- Kook SY, Jeong H, Kang MJ, Park R, Shin HJ, Han SH, Son SM, Song H, Baik SH, Moon M, Yi EC, Hwang D, Mook-Jung I. Crucial role of calbindin-D28k in the pathogenesis of Alzheimer's disease mouse model. Cell Death Differ. 2014 Oct;21(10):1575-87. Epub 2014 May 23 PubMed.
- Maya-Vetencourt JF, Carucci NM, Capsoni S, Cattaneo A. Amyloid plaque-independent deficit of early postnatal visual cortical plasticity in the 5XFAD transgenic model of Alzheimer's disease. J Alzheimers Dis. 2014;42(1):103-7. PubMed.
- Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher JR, Ficker WD, Yan P, Xiong C, Frederiksen C, Grzelak MV, Chott R, Bateman RJ, Morris JC, Mintun MA, Lee JM, Cirrito JR. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014 May 14;6(236):236re4. PubMed.