Mutations: APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type
Strain Name: C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax
Genetic Background: C57BL/6
Availability: Jackson Labs: Stock# 007027; Live
These transgenic mice express the human APP gene (isoform 770) containing the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations under the control of the mouse Thy1 promoter.
The mice develop fibrillar amyloid deposits primarily in the cerebral microvasculature starting at approximately six months. Aβ deposition also occurs in the brain parenchyma, generally in the form of diffuse plaque-like structures which begin at approximately 3 months of age in the subiculum, hippocampus and cortex and spread to the olfactory bulb and thalamic regions by 6 months. Aβ deposits are detected throughout the forebrain by twelve months (Davis et al., 2004). The mice also develop gliosis with a pronounced increase in the number of GFAP-positive astrocytes and activated microglia at 6-24 months, especially in the thalamus and subiculum, and to a lesser extent in the cortex (Miao et al., 2005).
Learning and memory deficits have been detected in homozygotes at 3, 9, and 12 months in the Barnes maze task. Beginning at three months, homozygotes took longer than wild-type C57Bl/6 mice to find the escape hole. No differences in mobility, strength or coordination were observed (Xu et al., 2007).
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
- Synaptic Loss
Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Amyloid-β deposits in the subiculum, hippocampus, and cortex at ~3 months. By ~6 months deposits become more numerous and appear in the olfactory bulb and thalamic region as well, with deposits throughout most of the forebrain by 12 months (Davis et al., 2004).
Pronounced increase in the number of GFAP-positive astrocytes and activated microglia with age (6-24 months) especially in the thalamus and subiculum and to a lesser extent in the cortex (Miao et al., 2005).
Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months; beginning at 3 months took longer to find the escape hole. No difference in mobility, strength or coordination (Xu et al., 2007).
- Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004 May 7;279(19):20296-306. PubMed.
- Miao J, Xu F, Davis J, Otte-Höller I, Verbeek MM, Van Nostrand WE. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005 Aug;167(2):505-15. PubMed.
- Xu F, Grande AM, Robinson JK, Previti ML, Vasek M, Davis J, Van Nostrand WE. Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice. Neuroscience. 2007 Apr 25;146(1):98-107. PubMed.
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