Mutations: APP KM670/671NL (Swedish)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: B6.Cg-Tg(Thy1-APP)3Somm/J
Genetic Background: C57BL/6
Availability: Available through The Jackson Laboratory Stock# 030504, Live
This widely-used and extensively characterized mouse model of AD was developed by researchers at Novartis and the University of Basel. These mice have a 7-fold overexpression of mutant human APP bearing the pathgenic Swedish mutation. The original publication also described two additional models: APP14, which similarly expresses the hAPP751 transgene bearing the Swedish mutation but utilizes the human Thy1 promoter, and APP22, which expresses APP with both the Swedish and London (V717I) mutations (Sturchler-Pierrat et al., 1997). The APP14 and APP22 models are no longer available. Data on this page refer to hemizygous APP23 animals. Homozygous APP23 mice on the C57BL/6 genetic background are viable but difficult to maintain as they breed less efficiently. Homozygotes reportedly develop amyloid pathology earlier and faster than hemizygotes (The Jackson Lab, May 2017).
These mice develop extensive β-amyloid pathology. Aβ deposits are first observed at six months of age. Congophilic plaques increase in size and number with age, occupying up to 25 percent of the neocortex and hippocampus in 24 month-old mice. Neocortical Aβ can been visualized with the PET tracer PiB at 12 months and beyond (Snellman et al., 2013). Plaques are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau, although neurofibrillary tangles are not observed. Neuronal loss has been reported in the CA1 region of the hippocampus. Mice also develop cerebral amyloid angiopathy (CAA), and microhemorrages occur at later ages (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998; Winkler et al., 2001). It has been reported that plaque development is faster in females than in males.
Deficits in spatial memory are observed in the Morris water maze at three months and become more severe with age (Van dam et al., 2003; Kelly et al., 2003). Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages (Kelly et al., 2003).
Age-associated changes in Aβ and tau levels in the cerebral spinal fluid (CSF) have been reported. The concentration of Aβ42 in the CSF is relatively stable until 16 months of age and then declines, with a 60 percent reduction measured by 30 months. The decrease in Aβ40 was less prominent. Total tau in the CSF was elevated in 24 to 26 month-old APP23 animals (Maia et al., 2013).
These transgenic mice express human APP (isoform 751) containing the Swedish (KM670/671NL) mutation under the murine Thy1 promoter.
Previously available through Novartis, now available through The Jackson Laboratory Stock# 030504, Live.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
Congophillic, dense-core amyloid plaques first appear at 6 months, and increase in size and number with age. Amyloid plaques can occupy more than 25% of the neocortex and hippocampus in 24 month-old mice (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998).
Dystrophic neurites containing hyperphopshorylated tau surounds Aβ plaques, but no neurofibrillary tangles are observed (Sturchler-Pierrat et al., 1997).
Neuronal loss (14-28%) has been reported in the CA1 region of the hippocampus in 14-18 month old mice (Calhoun et al., 1998).
Activated microglia in close proximity to dense amyloid plaques (Stalder et al., 1999). Upregulation of neuroinflammatory markers and activation of astrocytes and macrophages. Age-associated increase in components of the complement system, namely C1q and C3, at later ages (9 and 18 months, respectively) (Reichwald et al., 2009).
Neocortical synapses were examined in mice as old as 24 months of age; no evidence of alterations in the number of synapses or levels of synaptophysin were observed (Boncristiano et al., 2005).
Changes in LTP/LTD
LTP in the hippocampus and prefrontal cortex is normal at all ages studied: 3, 6, 9, 12, 18 and 24 months (Roder at al., 2003).
Spatial memory defects in Morris Water maze at 3 months and progresses with age (Van dam et al., 2003; Kelly et al., 2003).
- Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Bürki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13287-92. PubMed.
- Snellman A, López-Picón FR, Rokka J, Salmona M, Forloni G, Scheinin M, Solin O, Rinne JO, Haaparanta-Solin M. Longitudinal Amyloid Imaging in Mouse Brain with 11C-PIB: Comparison of APP23, Tg2576, and APPswe-PS1dE9 Mouse Models of Alzheimer Disease. J Nucl Med. 2013 Aug;54(8):1434-41. PubMed.
- Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, Staufenbiel M, Sommer B, Jucker M. Neuron loss in APP transgenic mice. Nature. 1998 Oct 22;395(6704):755-6. PubMed.
- Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci. 2001 Mar 1;21(5):1619-27. PubMed.
- Van Dam D, D'Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, De Deyn PP. Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci. 2003 Jan;17(2):388-96. PubMed.
- Kelly PH, Bondolfi L, Hunziker D, Schlecht HP, Carver K, Maguire E, Abramowski D, Wiederhold KH, Sturchler-Pierrat C, Jucker M, Bergmann R, Staufenbiel M, Sommer B. Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol Aging. 2003 Mar-Apr;24(2):365-78. PubMed.
- Maia LF, Kaeser SA, Reichwald J, Hruscha M, Martus P, Staufenbiel M, Jucker M. Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med. 2013 Jul 17;5(194):194re2. PubMed.
- Roder S, Danober L, Pozza MF, Lingenhoehl K, Wiederhold KH, Olpe HR. Electrophysiological studies on the hippocampus and prefrontal cortex assessing the effects of amyloidosis in amyloid precursor protein 23 transgenic mice. Neuroscience. 2003;120(3):705-20. PubMed.
- Reichwald J, Danner S, Wiederhold KH, Staufenbiel M. Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation. 2009;6:35. PubMed.
- Boncristiano S, Calhoun ME, Howard V, Bondolfi L, Kaeser SA, Wiederhold KH, Staufenbiel M, Jucker M. Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice. Neurobiol Aging. 2005 May;26(5):607-13. PubMed.
- Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M. Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol. 1999 Jun;154(6):1673-84. PubMed.
- Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC, Jucker M. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J Neurosci. 2011 Oct 12;31(41):14488-95. PubMed.
- Jiang H, He P, Xie J, Staufenbiel M, Li R, Shen Y. Genetic deletion of TNFRII gene enhances the Alzheimer-like pathology in an APP transgenic mouse model via reduction of phosphorylated IκBα. Hum Mol Genet. 2014 Sep 15;23(18):4906-18. Epub 2014 May 13 PubMed.
- Sommer B, Staufenbiel M. A beta peptide deposition in the brains of transgenic mice: evidence for a key event in Alzheimer's disease pathogenesis. Mol Psychiatry. 1998 Jul;3(4):284-6, 282-3. PubMed.