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: Jackson Labs: Stock# 006554; Live
These widely-used mice recapitulate many AD-related phenotypes and have a relatively early and aggressive presentation. This line (Tg6799) which expresses APP and PSEN1 at high levels, was generated along with two other lines with medium (Tg7031), and low (Tg7092), levels of expression. Tg6799 is now the most widely used 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 approcimately 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.
Jackson Labs: Stock# 008730 B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax
This congenic strain was generated by backcrossing to C57BL/6J mice. The retinal degeneration allele Pde6brd1 was bred out of the original strain. The phenotypes in the congenic strain are not identical to those in the B6SJL hybrid background (see data at MMRC).
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. PubMed.
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