APP transgenic Mouse Models

Alzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases of the 21st century. A disturbed APP metabolism (e.g. pathological aggregation of amyloid) in the brain of AD patients is thought to be one of the main causes of the observed progressive cognitive decline in affected people. The development of new AD drugs targeting APP related mechanisms is therefore one main focus in AD research. To be able to test these new drugs, appropriate animal models are needed.

QPS Neuropharmacology currently offers eight human APP transgenic mouse lines featuring different properties with regard to Aβ expression patterns, neuroinflammation, cognitive deficits, age at onset and progression of pathology. These animals focus on different pathological readouts and constitute suitable models to study the influence of drugs on APP-related brain pathology and behavior.

APPSL transgenic Mouse Model

APPSL transgenic mice overexpress human APP751SL under the control of the murine Thy1 promoter. This human APP with London (717) and Swedish (670/671) mutations is expressed in high levels, resulting in an age-dependent increase of β-amyloid1-40 and -42. Starting at 3 – 6 months APPSL mice develop plaques consisting of amyloid depositions in the frontal cortex.
Cognitive deficits of these mice start at 9 to 10 month of age. Additionally, APPSL animals present with severe neuroinflammation and oxidative stress starting as early as 6 and 9 month of age, respectively. This model presents with an unchanged motor performance. Animals were already frequently used for efficacy studies.

Figure 1: Assessment of spatial learning in the Morris water maze showing distance traversed and escape latencies during 4 testing days of 6 (A, D), 9 (B, E) and 12 month (C, F) old APPSL (orange) and wild type WT (blue) animals. n = 13-21. Mean ± SEM. Two-way ANOVA with Bonferroni‘s post hoc test compared to WT. *p<0.05; **p<0.01; ***p<0.001.

Figure 2: Qualitative comparison of APPSL transgenic mice at 6, 9 and 12 month of age vs. a 12 month old non transgenic animal. Images show examples of immunofluorescent labeling of 6E10 (green) and collagen IV (red) on brain sections of a APPSL transgenic mouse at 6 (column 2 – B,F), 9 (column 3 – C,G) and 12 month (column 4 -D,H) of age compared to a 12 month old non transgenic animal (column 1 – A,E); nuclei are labeled with DAPI (blue).

APPSL x hQC transgenic Mouse Model

QPS Neuropharmacology holds an exclusive license from Probiodrug AG for APPSL x hQC mice, which are crossbreds of  APPSL and hQC mice (Jawhar et al., 2011). Both transgenes are under the regulatory control of the Thy1 promoter and both mouse lines have a pure C57BL/6xDBA background.
The cross breeding of APPSL and hQC mice results in an increased generation of N-terminal modified pGlu Aβ peptides and allows the analysis of neurodegenerative events that depend on specific pGlu Aβ enzymatic activity in vivo. These mice are an efficient model to analyze pGlu Aβ modifying drugs in vivo. Additionally, double transgenic APPSL x hQC mice present with the same pathologies as APPSL mice, like plaque formation, neuroinflammation and cognitive deficits, but most symptoms appear a little earlier as in single transgenic APPSL mice. This model presents with an unchanged motor performance.
APPSL x hQC mice are thus a good tool to study pGlu Aβ dependent effects on cognition and histological parameters at an early age of 6 months. An additional readout of APPSL x hQC mice are hQC levels.

Figure 1: Morris water maze of 6 month old APPSL x hQC mice compared to non-transgenic littermates. Escape latency in seconds. Mean ± SEM. n = 4-8. Two-way ANOVA with Bonferroni’s post hoc test. **p<0.01; ***p<0.001.     
Figure 2: pGluAβ levels in the cortex of APPSL x hQC mice over age. Aβ3(pE)-40/42 quantification (>150 µm² plaque size) with an anti human pGlu Aβ antibody. Mean + SEM. One-way ANOVA. *p<0.05, ***p<0.001. n = 4 – 8.


ApoB x APP transgenic Mouse Model

These mice are crossbreds of APPSL and Apo-B100 mice overexpressing the entire 43 kb human apolipoprotein B-100 gene (ApoB-100; Bjelik et al., 2006) including its natural human promoter. These mice show all pathological features of APPSL mice and additionally increased LDL-cholesterol and decreased HDL-cholesterol levels. Cortical oxidative stress starts already at the age of 6 months in double transgenic mice. Additionally, at the same age ApoB x APP mice show a strong accumulation of ApoB100 in cerebral vessels and astrogliosis in the hippocampus. This model presents with an unchanged motor performance.
The ApoB x APP transgenic mouse line is a suitable model for vascular disease dependent amyloidogenic Alzheimer’s disease research, since it illustrates major biochemical and behavioral hallmarks of AD (Löffler et al., 2013).

Figure 1: Plasma lipid profile of 6 month old ApoB x APP transgenic animals. Total cholesterol (A), triglyceride (B), HDL cholesterol (C), and LDL cholesterol after Friedewald (D) in percent relative to non-transgenic littermates (WT). n = 13 – 18. One-Way ANOVA with Bonferroni’s post hoc test. *p<0.05; **p<0.01; ***p<0.001.

5xFAD transgenic Mouse Model

5xFAD (Familiar Alzheimer Disease) mice bear 5 mutations, 3 in the APP695 gene [APP K670N/M671L (Swedish), I716V (Florida), V717I (London)] as well as 2 mutations in the presenilin 1 gene [PS1 M146L, L286V] (Oakley et al., 2006). The expression of the 5xFAD transgene is driven by the neuron-specific Thy1 promoter.
5xFAD transgenic mice highly overexpress Aβ1-40 and Aβ1-42 in the brain and cerebrospinal fluid which even increases over age. Histological analyses of the cortex and hippocampus revealed a dramatic plaque load and β-sheet formation accompanied by strong neuroinflammation. These pathological hallmarks also significantly increase over age. Animals present spatial and long term memory deficits as analyzed by the Morris water maze. Motor deficits were not detected.
5xFAD mice are thus a suitable model to study the influence of drugs on amyloid production, sequestration and deposition, the involvement of presenilin1 and inflammation.

Figure 1: Aβ42 level in the cortex (A) and hippocampus (B) of 3-, 6- and 9-month old 5xFAD mice. Immunoreactive (IR) area in percent; n = 3. Mean + SEM. One-way ANOVA with Bonferroni’s post hoc test. **p<0.01; ***p<0.001.

Figure 2: Quantification of neurofilament light chain in plasma and CSF of 5xFAD mice. A: NF-L levels in pg/ml in the plasma of 3, 6, 9 and 12 month old 5xFAD mice compared to non-transgenic littermates. Mean +SEM; n = 4-8. Two-way ANOVA with Bonferroni‘s post hoc test. B: Activated microglia in the cortex of 3, 6 and 9 month old 5xFAD mice. Immunoreactive area in percent in the cortex; n = 3. Mean + SEM. One Way ANOVA with Bonferroni’s post hoc test. *p<0.05; **p<0.01; ***p<0.001.

TBA2.1 transgenic Mouse Model

The human TBA2.1 transgenic mouse model is suitable to model AD related neuronal loss and neurodegeneration and thus late stage AD. The model was developed by Alexandru and colleagues.
This AD transgenic mouse model over expresses truncated mutated human Aβ(Q3-42) under the control of a neuron specific Thy1 promoter with a C57BL/6xDBA1 background. Aβ(Q3-42) is fused to pre-pro-TRH for product release within the secretory pathway. Quantification of pE3-Aβ protein levels show a peak of pE3-Aβ levels at the age of 1 month and afterwards decreasing. While Aβ quantification shows a continuous increase of Aβ levels over age. Homozygous TBA2.1 animals further present a severe neuronal loss in the hippocampal medial CA1 region.

Figure 1. A: Hippocampal pyramidal cell loss in the CA1 region of 5 month old heterozygous and homozygous TBA2.1 mice. Region size in mm2 in the CA1 region. One-way ANOVA with Bonferroni’s post hoc test. n = 6 per group. Mean ± SEM. *p<0.05; **p<0.01. B: Aβ42 immunoreactivity in the hippocampus of 5 months old homozygous TBA2.1 mice. Tissue was immunofluorescently labeled with H31L21 antibody and analyzed for immunoreactive area in percent. Mean + SEM; n = 5; unpaired t-test; ***p<0.001.

Figure 2. Astrocytosis in the hippocampus of 3 month old homozygous TBA2.1 mice. GFAP (green) and DAPI (red) labeling of homozygous TBA2.1 mice (B) compared to non-transgenic littermates (A). cc: corpus callosum; so: stratum oriens; sp: stratum pyramidale; sr: stratum radiatum.

Tg4-42 (TBA83) Mouse Model

This AD transgenic mouse model over expresses N-truncated human Aβ(4-42) under the control of the neuron-specific Thy1 promoter with a C57BL/6 J background. The Tg4-42 (TBA83) mouse model is suitable to model AD related neuronal loss and neurodegeneration and thus late stage AD. Animals present high Aβ42 levels in the hippocampal CA1 region in 3 month old hemizyous Tg4-42 mice  with an age-dependent reduction in positive cells. Increased astrogliosis and microgliosis can be observed as early as 2 months in hemizygous Tg4-42 mice.

Figure 1: Morris water maze of 12 months old Tg4-42 mice. Escape latency in seconds (A) and abidance in the target sector in percent (B). Mean ± SEM; n = 4-10. Two-way ANOVA with Bonferroni´s post hoc test : *p<0.05, **p<0.01, ***p<0.001.

Figure 2: A: Quantification of Aβ42 expression in 12 month old homozygous and hemizygous mice compared to non-transgenic littermates. Mean + SEM. One-way ANOVA with Bonferroni‘s post hoc test. **p<0.01; ***p<0.001 B: Aggregated Aβ42 levels in brain homogenates of 3-12 month old Tg4-42 mice. Aggregated Aβ42 levels were measured by A4 assay and are shown in pg/mg. ntg animals are not shown.

Tg2576 Mouse Model

Tg2576 are commercially available from Taconic and will be purchased after study initiation.

QPS Neuropharmacology offers custom tailored study design for these models and we are flexible to accommodate to your special interests. We are also happy to advice you and propose study designs. QPS Neuropharmacology maintains its own colonies directly in our research facility. Non-transgenic littermates are available as control animals needed for proper study design.

We would be happy to test your compounds in these mouse models! Readouts depend on model but the most common are:

  • Aβ-38,-40 and -42 levels
  • Aggregated Amyloid levels by A4 Assay
  • Plaque load
  • β-sheet load
  • pE(3)-Aβ load
  • Neurofilament Light Chain levels
  • Neuronal loss
  • Synaptic alterations
  • Oxidative stress
  • Neuroinflammation
  • Cerebral vascular angiopathy (CAA)
  • Phosphorylated tau
  • Blood brain barrier homeostasis
  • Learning and memory deficits (MWM)
  • Looking for something else? Please contact us!

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As with all other in vivo models we are also ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory.

We are happy to receive your inquiry.