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 for the observed progressive cognitive decline in affected people. The development of new AD 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 Austria currently offers seven 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.

QPS Austria offers custom tailored study designs for these models and we are flexible to customize to your special need. We are also happy to advise you and propose previously successful study designs. A typical turnaround time from agreement to the study plan to the final report is about 4 months. QPS Austria maintains its own colonies directly in our research facility, and animals of all age groups are typically available without any long latency. This allows for extraordinarily fast turn-around times. Non-transgenic control littermates are available as needed for proper study design.

We would be happy to test your compounds in our APP transgenic mouse models! The most common readouts are:

•    Soluble and insoluble Aβ levels
•    Aβ Oligomers
•    APP plaques
•    LOC
•    Thioflavin S
•    Neuroinflammation
•    Cognition
•    Looking for something else? Please contact us!


APPSL tg Mouse Model

APPSL transgenic mice over-express human APP751SL under the control of the murine Thy-1 promoter. The animals contain the same gene construct as described in Rockenstein et al. (2001). This human APP with London (717) and Swedish (670/671) mutations is expressed in high levels, resulting in an age-dependent increase of beta-amyloid1-40 and beta-amyloid1-42, the pathologically relevant forms of amyloid protein. The mice develop plaques consisting of amyloid depositions in early age, starting at 3 – 6 months in the frontal cortex. Severity of the brain pathology correlates with increasing age and behavioral deficits. Cognitive deficits of these mice include spatial and emotional learning as well as long term memory deficits (Havas et al., 2011). Additionally, APPSL animals present with severe neuroinflammation and oxidative stress starting as early as 6 and 9 months of age, respectively (Löffler et al., 2014). The modifiability of several of these pathologies was already shown in a whole series of treatment studies (Windisch et al., 2013). This model presents with an unchanged motor performance.

QPS Austria's APP tg mice are a suitable model to study the influence of drugs on amyloid production, sequestration and deposition. 

Qualitative comparison of plaque pathology of APPSL transgenic mice at 3, 6 and 9 months of age

Qualitative comparison of plaque pathology of APPSL transgenic mice at 3, 6 and 9 months of age. Tissue was labeled with antibody 6E10. Longitudinal testing of 3-9 months old APPSL transgenic mice in the Poke hole test compared to non-transgenic littermates. Curiosity is measured in seconds that animals spend poking their nose into a hole. Animals were repeatedly used for each time point (longitudinal).

Curiosity is measured in seconds that animals spend poking their nose into a hole. Animals were repeatedly used for each time point (longitudinal) 

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APPSL x hQC tg Mouse Model

APPSL x hQC mice 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. 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. To our knowledge, these transgenic mice are the only efficient model to analyze pGlu Aβ modifying drugs in vivo.

An additional readout of APPSL x hQC mice are hQC levels.

Escape latency in the Morris Water of 6 months old APPSL x hQC mice compared to non transgenic littermates and pGlu Aβ levels in the hippocampus of APPSL x hQC mice over age

Escape latency in the Morris Water of 6 months old APPSL x hQC mice compared to non transgenic littermates and pGlu Aβ levels in the hippocampus of APPSL x hQC mice over age. Data are represented as mean ± SEM. 5.5 months: 8 APPSL x hQC; 7.5 months: 8 APPSL x hQC; 9.5 months: 8 APPSL x hQC; 12.5 months: 8 APPSL x hQC; 22 months: 4 APPSL x hQC.

APPSL and hQC mice results in an increased generation of N-terminal modified pGlu Aβ peptides

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APPSL x ApoB-100 tg Mouse Model

These mice are crossbreds of APPSL mice and Apo-B100 mice overexpressing the entire 43 kb human apolipoprotein B-100 (ApoB-100; Bjelik et al., 2006) gene including its natural human promoter. These mice present with all pathological features of APPSL mice and additionally show 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 APPSL x ApoB-100 mice show a strong accumulation of ApoB100 in cerebral vessels and astrogliosis in the hippocampus. This model presents with an unchanged motor performance.

The APPSL x Apo-B100 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).

Additional readouts of APPSL x ApoB-100 mice are:

•    LDL- and HDL- cholesterol levels
•    Cerebral accumulation of ApoB-100 in leptomeningeal vessels

Plasma lipid profile of 6 months old APPSL x ApoB-100 transgenic animals. LDL levels after Friedewald, and HDL levels are shown in percent relative to non-transgenic littermates. Plasma lipid profile of 6 months old APPSL x ApoB-100 transgenic animals. LDL levels after Friedewald, and HDL levels are shown in percent relative to non-transgenic littermates. A: APPSL x ApoB-100; B: ApoB-100; C: APPSL; D: non-transgenic littermates. A: N= 13, B: N=18, C: N=16, D: N=18. *P<0.05; **P<0.01; ***P<0.001. One-Way ANOVA followed by Bonferroni’s Multiple Comparison Test.

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5xFAD tg 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 beta 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 although analyzed by several motor tests.

All 5 gene mutations of this animal model are known to occur in humans. 5xFAD tg mice are thus a suitable model to study the influence of drugs on amyloid production, sequestration and deposition, the involvement of presenilin1 and inflammation.

Aβ plaque load quantification in the cortex and hippocampus of 3 and 9 months old 5xFAD transgenic mice. Aβ plaque load quantification in the cortex and hippocampus of 3 and 9 months old 5xFAD transgenic mice. Number of objects per mm2 in the cortex (left panel) and hippocampus (right panel). N =5. Data are shown as mean ±SEM. Data were analyzed by t-test. **p<0.01; ***p<0.001.

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TBA2.1 tg Mouse Model

Experts in the field have debated for decades whether amyloid-beta or TAU is the better target to cure Alzheimer’s Disease (AD). We cannot not answer this question, but QPS Austria can offer an extensive CRO service with transgenic mouse models for both aspects of the disease.

The human TBA2.1 transgenic mouse model is suitable to model AD related neuronal loss and neurodegeneration and thus late stage AD.

The mice were recently developed and characterized by Alexandru and colleagues. By now, the mouse model is settled in our animal facility and breeding is ongoing. Due to its novelty, so far no data are published about the suitability of this model to test new compounds against AD.

This AD transgenic mouse model over-expresses truncated mutated human Aβ(Q3-42) under the control of a neuron specific mThy1.2 promoter with a C57BL/6xDBA1 background. Aβ(Q3-42) is fused to pre-pro-TRH for product release within the secretory pathway (Alexandru et al., 2011). Quantification of pE3-Aβ protein levels show a peak of pE3-Aβ levels at the age of 1 month and afterwards decreasing. Aβ quantification on the other hand, shows a continuous increase of Aβ levels over age (Alexandru et al., 2011). Homozygous TBA2.1 animals further present with a severe neuronal loss in the hippocampal medial CA1 region (Fig.1 and Alexandru et al., 2011), depending on a reduced number of pyramidal cell somata and thus a reduced thickness of the stratum pyramidale (Fig.1, 2 and Alexandru et al., 2011).

The size of CA1 is reduced in 5 months old homozygous TBA 2.1 mice compared to non-transgenic littermates; the size in heterozygotes is intermediate. NeuN-immunoreactivity is reduced in homozygous mice, indicating loss of pyramidal cells in medial CA1.
Figure 1: Neurodegeneration in 5 months old homozygous and heterozygous TBA2.1 mice. CA1 region size (A). NeuN-immunoreactivity of the CA1 region (B).

At the age of 3-5 months, astrogliosis and microgliosis as indicator of neuroinflammation are highly increased in homozygous TBA2.1 mice (Fig.2 and Alexandru et al., 2011).

The number of pyramidal cell somata is reduced in the medial CA1 of the hippocampus in 5 months old homozygous TBA 2.1 mice compared to non-transgenic littermates, as evident from the reduced thickness of the stratum pyramidale. GFAP-positive astrocytes are more frequent in TBA 2.1 mice.
Figure 2: Astrocytosis in 5 months old homozygous TBA2.1 mice. (A) Reduced thickness (arrowheads) of stratum pyramidale (sp). (B) GFAP-positive astrocytes in TBA 2.1 mice. Abbreviations: corpus callosum (cc), strata oriens (so) and radiatum (sr).

Additionally, 5 months old homozygous TBA2.1 mice have strong synaptic dysfunctions as shown by a diminished LTP and fEPSP amplitude (Fig.3 taken from Alexandru et al., 2011).

LTP of 5 months old homozygous TBA2.1 mice is significantly reduced compared to non-transgenic littermates. Additionally, the fEPSP amplitude of 5 months old homozygous TBA2.1 mice is significantly reduced when compared with non-transgenic littermates. [1]
Figure 3: Synaptic dysfunction of TBA2.1 mice. LTP of fEPSP after application of strong tetanus at time point 0. (A) LTP of 5 months old homozygous TBA2.1 mice compared to non-transgenic littermates. (B) fEPSP amplitude of 5 months old homozygous TBA2.1 mice compared to non-transgenic littermates. [1]

Behavioral characterization of homozygous TBA2.1 mice reveals a reduced free feeding and drinking behavior, slowed body weight gain and severely disturbed hanging behavior, righting reflex and motor deficits as analyzed by RotaRod starting at early age. Furthermore, already 1 month old animals present with a significantly reduced prepulse inhibition of the auditory startle reflex (Alexandru et al., 2011). For further details about TBA2.1 mice, please see Alexandru et al., 2011.

Due to the severe neuronal loss and synaptic dysfunction of homozygous TBA2.1 mice, this transgenic mouse model reflects the ideal tool for the study of pE3-Aβ depending neurodegeneration and the analysis of new compounds against late stage AD.

QPS Austria offers custom tailored study design for this model and we are flexible to accommodate to your special interest. We are also happy to advice you and propose study designs. A typical turnaround time from agreement to the study plan to the final report is about 6 months. QPS Austria maintains its own colony directly in our research facility. Animals are typically available without any long latency. Compared to other APP transgenic mouse lines, the TBA2.1 line shows relevant features of late stage AD already at young age. This allows for extraordinarily fast turn-around times. Furthermore, heterozygous and non-transgenic littermates are available as control animals needed for proper study design.

We would be happy to test your compounds in our Aβ(Q3-42) transgenic mouse model! The most common readouts are:

•    Neuronal loss and neurodegeneration
•    Neuroinflammation
•    Synaptic dysfunctions
•    Prepulse Inhibition
•    Looking for something else? Please contact us!

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Tg4-42 (TBA83) Mouse Model

This Alzheimer's Disease (AD) transgenic mouse model over-expresses N-truncated human Aβ(4-42) under the control of a neuron specific mThy1 promoter with a C57BL/6 J background. Aβ(4-42) is fused to pre-pro-TRH enabling its extracellular release.

The Tg4-42 (TBA83) mouse model is suitable to model AD related neuronal loss and neurodegeneration and thus late stage AD.
Characterization of Tg4-42 mice by Bouter et al. 2013 [1]:
  • Strong Aβ42 immunostaining in CA1 in 3 months old hemizyous Tg4-42 mice  with an age-dependent reduction in positive cells

Strong Aβ42 immunostaining in CA1 in 3 months old hemizyous Tg4-42 mice  with an age-dependent reduction in positive cells

  • Further Aβ42 positive areas: occipital cortex, piriform cortex, striatum, superior colliculus
     
  • Increased astrogliosis and microgliosis as early as 2 months in hemizygous Tg4-42 mice
     
  • Age and dose dependent neuron loss in the hippocampus of Tg4-42 mice (see right)
Characterization by QPS Austria:
  • Spatial learning and memory deficits in the Morris water maze starting at 10 months
Spatial learning and memory deficits in the Morris water maze starting at 10 months
 

Age and dose dependent neuron loss in the hippocampus of Tg4-42 mice

[1] Bouter et al. N-truncated amyloid (Aβforms stable aggregates and induces acute and long-lasting behavioral deficits. Acta Neuropathol (2013) 126:189-205. 

 

 

QPS Austria offers custom tailored study design for this model and we are flexible to accommodate to your special interest. We are also happy to advice you and propose study designs.

We would be happy to test your compounds in our Tg4-42 (TBA83) mouse model! 

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Tg2576 Mouse Model

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

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Alternative model

QPS Austria offers alternative models allowing the performance of similar types of studies like APPSL and 5xFAD transgenic mice or any other commercially available mouse line.
You might also be interested in these related topics

•    In vitro AD models
•    Scopolamine induced AD mouse model
•    Amorfix Aggregated Aβ Assay (A4)
•    Intracerebral β-amyloid injections in rats

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.

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