Mutations: APP KM670/671NL (Swedish)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6;SJL-Tg(APPSWE)2576Kha
Genetic Background: Founder Line: 2576, backcrossed to C57BL/6
Availability: Taconic Stock #1349 and Charles River Tg2576
The human APP gene (isoform 695) containing the double mutation K670N, M671L (Swedish mutation) under the control of the hamster prion protein.
Tg2576 mice overexpress a mutant form of APP (isoform 695) bearing the Swedish mutation (KM670/671NL). This model was originally developed by Karen Hsiao Ashe and are now maintained at Taconic and Charles River. The mice develop numerous parenchymal Aβ plaques by 11-13 months with some vascular amyloid. They also show oxidative lipid damage but no evidence of neurofibrillary tangles. Cognitive function has been extensively characterized in this model. Impaired learning at a spatial task, working memory and contextual fear conditioning have been reported at less than six months although other studies have reported normal cognition at this age with progressive impairment at 12 months. Dendritic spine loss has been reported by 4.5 months in the CA1 region of the hippocampus.
Changes in synaptic plasticity have been noted in this model. By five months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type animals. No deficit was observed at two months (Jacobsen et al., 2006). LTP in both the CA1 and dentate gyrus of aged mice (greater than 15 months) is impaired (Chapman et al., 1999), but differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).
Taconic: Stock# 002789 (129 background)
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
Numerous parenchymal Aβ plaques by 11-13 months.
Absent or very limited.
Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).
Dendritic spine loss by 4.5 months In the CA1 region of the hippocampus (Lanz et al., 2003).
Changes in LTP/LTD
By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).
Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.
- Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5161-6. PubMed.
- Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci. 1999 Mar;2(3):271-6. PubMed.
- Jung JH, An K, Kwon OB, Kim HS, Kim JH. Pathway-specific alteration of synaptic plasticity in Tg2576 mice. Mol Cells. 2011 Aug;32(2):197-201. PubMed.
No Available Further Reading