Research Models

APP23

Synonyms: B6-Tg/Thy1APP23Sdz

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Species: Mouse
Genes: APP
Mutations: APP KM670/671NL (Swedish)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: N/A
Genetic Background: C57BL/6
Availability: Available through Material Transfer Management at Novartis

This widely-used and extensively characterized model was developed by colleagues at Novartis Pharma and the University of Basel. Mice have a 7-fold overexpression of mutant human APP carrying the Swedish mutation. The original publication (Sturchler-Pierrat et al., 1997) 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. The APP14 and APP22 models are no longer available.

Modification Details

Transgene containing human APP (isoform 751) containing the Swedish (KM670/671NL) mutation under the murine Thy1 promoter. 

Neuropathology

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 no neurofibrillary tangles are observed. Neuronal loss has been reported in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998; Winkler et al., 2001).

Cognition/Behavior

Spatial memory defects in Morris Water maze at three months and progresses with age (Van dam et al., 2003; Kelly et al., 2003). Memory deficits in passive avoidance (shock) test were observed in 25 month-old mice, but not at younger ages (Kelly et al., 2003).

Other Phenotypes

The CSF levels of Aβ and tau have also been examined. Aβ42 concentrations in CSF remain unchanged until 16 months, and then decline, with a 60 percent reduction by six months of age. Decreases in Aβ40 CSF concentrations were less prominent. CSF concentration of total tau is also elevated in 24-26 month-old APP23 animals (Maia et al., 2013).

Availability

For information regarding the availability of this model contact Material Transfer Management at Novartis.

Phenotype Timeline

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Observed

Absent

  • Tangles
  • Synaptic Loss
  • Changes in LTP/LTD

Unknown

Plaques

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).   

Tangles

Dystrophic neurites containing hyperphopshorylated tau surounds Aβ plaques, but no neurofibrillary tangles are observed (Sturchler-Pierrat et al., 1997).

Neuronal Loss

Neuronal loss (14-28 percent) has been reported in the CA1 region of the hippocampus in 14-18 month old mice (Calhoun et al., 1998).     

Gliosis

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 months and 18 months, respectively) (Reichwald et al., 2009). 

Synaptic Loss

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).

Cognitive Impairment

Spatial memory defects in Morris Water maze at 3 months and progresses with age (Van dam et al., 2003; Kelly et al., 2003).

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References

Paper Citations

  1. . 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.
  2. . 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.
  3. . Neuron loss in APP transgenic mice. Nature. 1998 Oct 22;395(6704):755-6. PubMed.
  4. . Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci. 2001 Mar 1;21(5):1619-27. PubMed.
  5. . Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci. 2003 Jan;17(2):388-96. PubMed.
  6. . Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiol Aging. 2003 Mar-Apr;24(2):365-78. PubMed.
  7. . 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.

Other Citations

  1. Material Transfer Management at Novartis

Further Reading

News

  1. Cerebrospinal Fluid Tau Climbs in Aβ Mouse Models

Papers

  1. . 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.
  2. . Expression of complement system components during aging and amyloid deposition in APP transgenic mice. J Neuroinflammation. 2009;6:35. PubMed.
  3. . Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice. Neurobiol Aging. 2005 May;26(5):607-13. PubMed.
  4. . Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol. 1999 Jun;154(6):1673-84. PubMed.
  5. . Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J Neurosci. 2011 Oct 12;31(41):14488-95. PubMed.