Mutations: APP K670_M671delinsNL (Swedish), APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Hybrid C3H/He-C57BL/6
Availability: Available through the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto
These transgenic mice overexpress mutant human APP at levels approximately 5-fold higher than endogenous murine APP. As the mouse ages, levels of "human" Aβ40 and Aβ42 increase, with Aβ42 being the more prevalent species (Chishti et al., 2001). These mice develop early plaque formation with thioflavin S-positive amyloid deposits observed at three months and dense-cored plaques with neuritic pathology by five months, becoming more extensive with advanced age. Activated microglia appear concurrently with plaques and GFAP-positive astrocytes follow later, starting about 13-14 weeks (Dudal et al., 2004). Dystrophic neurites are also observed (Dudal et al., 2004; Woodhouse et al., 2009). There is a decrease in the number of cholinergic neurons in the nucleus basalis magnocellularis as measured by ChAT immunoreactivity (Bellucci et al., 2006) and loss of glutamic acid decarboxylase (GAD)-immunoreactive GABAergic neurons (Krantic et al., 2012).
Behaviorally, these mice show a variety of impairments, including early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze, by three months of age (Chishti et al., 2001). Age-associated cognitive deficits are observed in the step-down inhibitory avoidance test (deficits at seven months, but not at two months). No differences from wild-type mice were observed in motility, exploratory activity, or neuromuscular function at seven months as evaluated by the rotarod, hole board, and grip strength tests (Bellucci et al., 2006). In addition, susceptibility to seizure (Del Vecchio et al., 2004) and LTP-related changes (Jolas et al., 2002; Kimura et al., 2012) have been reported.
Survival rates depend on the genetic background. Survival on the (C57) × (C3H/C57) genetic background was the highest, with 50 percent of mice surviving until postnatal day 365 (the upper limit in the analysis. Mice on the (C3H/C57/129SvEv/Tac) × (129SvEv/Tac) and (FVB)×(C3H/C57) had increased mortality with 25 percent and 17 percent respectively reaching 365 days (Chishti et al., 2001).
Aβ42 immunization reduced deposition of cerebral fibrillar Aβ and improved cognitive dysfunction (Janus et al., 2000).
Transgene contains human APP695 with the Swedish mutation (KM670/671NL) and Indiana mutation (V717F) under the control of the hamster prion (PrP) gene promoter. The expression cassette includes about 90 nucleotides of the APP 5'-untranslated region adjacent to the start codon and 269 nucleotides of the 3′-untranslated region.
Available through the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto (firstname.lastname@example.org).
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 progresses with age. Thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques appear first in the subiculum, amygdala and frontal cortex, spread to the dentate gyrus, the olfactory bulb, and later thalamus, cerebral vasculature, and striatum, followed by the cerebellum and brain stem (Chishti et al., 2001).
Neurofibrillary tangles are absent (Chishti et al., 2001). Tau is hyperphosphorylated, nitrosylated and aggregated at 7-12 months especially in the neocortex, dentate gyrus, and the CA1 and CA3 areas of the hippocampus (Bellucci et al., 2007).
Variable cell loss by region. No difference in overall cell count, but fewer hippocampal neurons at 6 months (Brautigam et al., 2012).
Microglia activation appears simultaneously with Aβ deposition, with only rare activated microglia at 9-10 weeks, but by 13-14 weeks microglia cluster around Aβ deposits in the cerebral cortex and hippocampus; numerous by 20 weeks. Robust astrogliosis slightly later with clusters of GFAP+ astrocytes emerging around plaques at 13-14 weeks (Dudal et al., 2004).
Reduced synaptophysin immunoreactivity in the vicinity of plaques at 6 months (Adalbert et al., 2009).
Changes in LTP/LTD
In hippocampal slices from 6- to 12-month-old mice basal excitatory synaptic transmission (as assessed by I/O relationships) and LTP at CA1 are reduced in TgCRND8 mice compared with wild-type mice (Kimura et al., 2012).
Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months (Chishti et al., 2001).
Last Updated: 08 Nov 2013
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