Mutations: APP E693del (Osaka)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: B6C3F1, back-crossed to C57Bl/6
Availability: Available through Hiroshi Mori and Takami Tomiyama
This transgenic mouse expresses human APP with the E693Δ mutation, a deletion mutation associated with early onset Alzheimer’s disease in several Japanese individuals. This mutation, also called the Osaka mutation, involves the in-frame deletion of a codon in exon 17, resulting in a missing glutamate at position 693 in APP, and at position 22 in resulting Aβ peptides.
The E693Δ mouse model is notable for accumulating Aβ within neurons of the hippocampus and cortex. This intraneuronal Aβ is thought to exist largely in oligomeric form, as demonstrated by immunohistochemistry with an oligomer-specific antibody and fractionation of the cortex followed by immunoprecipitation and western blot (Tomiyama et al., 2010). Despite the enhanced oligomerization of E693Δ Aβ peptides, these mice do not develop extracellular amyloid deposits, even at advanced ages, consistent with in vitro reports of minimal fibril formation of Aβ peptides with the Osaka mutation (Tomiyama et al., 2008). Despite the lack of extracellular plaque pathology, E693Δ mice develop age-associated memory deficits, synaptic deficits, neuronal loss, and tau hyperphosphorylation (Tomiyama et al., 2010). The E693Δ mouse is considered a useful model for investigating Aβ oligomer-related pathologies and for piloting oligomer-targeted therapies.
According to the initial report, three lines of APP E693Δ transgenics were generated. Line 1 is the best-characterized of the three and is the focus of this description. All three lines express low levels of the transgene, with line 1 expressing the highest levels, roughly equivalent to endogenous murine APP, and about 1/10 the transgene expression seen in the Tg2576 mouse. Unless otherwise noted, the data described on this page refer to heterozygous animals. It is not known if homozygous mice are viable or if disease-related phenotypes would be more severe or accelerated in the homozygous state (personal communication, Takami Tomiyama).
Although this model develops hyperphosphorylated tau, it does not develop overt tangle pathology. However, when crossed with the Tau264 model, which expresses low levels of human tau, the double transgenics develop neurofibrillary tangles by 18 months of age. In addition, the presence of human tau in the double transgenic accelerates the pathologies observed in the APP E693Δ single transgenic, including Aβ oligomer accumulation, synapse loss, neuronal loss, and memory impairment (Umeda et al., 2014).
This transgenic model expresses low levels of human APP (isoform 695) carrying the Osaka mutation and driven by the mouse prion promoter.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Neuronal loss, as measured by NeuN staining, was observed in the CA3 region of the hippocampus at 24 months of age. Neuronal loss was not detected in the cerebral cortex at this time.
Extracelluar amyloid plaques are not observed out to 24 months; however, Aβ accumulates within neurons of the hippocampus and cerebral cortex starting around eight months of age.
Overt tangle pathology is not observed out to 24 months of age, but abnormal tau phosphorylation is observed starting around eight months of age.
At 12 months of age, microgliosis is seen in transgenic mice, as measured by the presence of Iba-1 staining in the hippocampus and cortex. Astrocytosis, as measured by GFAP-reactivity, increased starting around 18 months of age in these regions.
Starting around eight months of age, transgenic mice exhibit a decrease in synaptic density in the CA3 region of the hippocampus as measured by synaptophysin staining.
Changes in LTP/LTD
By eight months of age, transgenic mice exhibit reduced short term plasticity as measured by paired-pulse facilitation in addition to reduced LTP as elicited by high frequency stimulation to the perforant pathway.
By 8 months of age, transgenic mice exhibit memory impairment in the Morris water maze compared to mice expressing equivalent levels of wild-type human APP.
Research Models Citations
- Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci. 2010 Apr 7;30(14):4845-56. PubMed.
- Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H. A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia. Ann Neurol. 2008 Mar;63(3):377-87. PubMed.
- Umeda T, Maekawa S, Kimura T, Takashima A, Tomiyama T, Mori H. Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol. 2014 May;127(5):685-98. Epub 2014 Feb 15 PubMed.
- Umeda T, Tomiyama T, Sakama N, Tanaka S, Lambert MP, Klein WL, Mori H. Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. J Neurosci Res. 2011 Jul;89(7):1031-42. PubMed.
- Umeda T, Tomiyama T, Kitajima E, Idomoto T, Nomura S, Lambert MP, Klein WL, Mori H. Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice. Life Sci. 2012 Jan 17; PubMed.