Transgenic Mouse Models

TRANSGENIC MOUSE MODEL
Overview

QPS Neuropharmacology is experienced in generating, characterizing and maintaining of transgenic disease models and using them for drug testing projects for more than 15 years.

The mouse and rat models available for drug development in Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Niemann-Pick Disease, Gaucher Disease, Amyotrophic Lateral Sclerosis (ALS) , Autism Spectrum Disorder (ASD), Schizophrenia, Frontotemporal Lobar Degeneration (FTLD), and other neurodegenerative diseases allow the quantitative evaluation of compound interactions with amyloid, tau, inflammation related markers, mitochondrial deficiency and other pathologies.

We are happy to receive any inquiry to elaborate the most efficient way, including behavioral, immunohistochemical, biochemical and molecular biological techniques, for the support of your drug development approach.

Our biobank can provide samples (brain tissue, CSF, etc.) of our animal models for analyses in your laboratory.

ALPORT SYNDROME

Alport syndrome is a hereditary disorder of the basement membrane, resulting in a glomerulonephropathy causing renal failure. Progressive deafness and ocular anomalies may also occur (Mochizuki et al. 1994; Colville et al. 1997). Patients with Alport syndrome were reported to show mutations in collagen IV genes (Mochizuki et al.1994; Lemmink et al. 1994 and 1997; Gubler et al. 1995). Approximately 85% of cases of Alport syndrome are X-linked and are related to mutations in the Col4a5 gene. About 14% are autosomal recessive forms that are caused by mutations in Col4A3 and Col4A3 genes, while autosomal dominant inheritance is rare (van der Loop et al., 2000).

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ColA43 KNOCKOUT MOUSE MODEL

Mice homozygous for the Col4A3-/- targeted mutation are a model for autosomal-recessive Alport syndrome (Cosgrove et al. 2007). Animals bred on a 129/SvJ background develop glomerulonephritis and die at about 8.5 weeks of age (Jackson Laboratory strain: #002908). Gross et al. (2003) reported a mean survival of 10 weeks. Since homozygous Col4a3-/- mice reflect key features of Alport syndrome, this mouse model is useful to test potential drug candidates.

Typical analysis parameters are:

  • Renal Smooth muscle actin
  • Renal Periodic acid–Schiff (PAS) staining for polysaccharides
  • Blood analyses
  • Ability to urinate
  • Survival
QPS Austria is ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory.

AMYOTROPHIC LATERAL SCLEROSIS

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 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 colony directly in our research facility. Animals of all age groups are typically available without any long delay. Non-transgenic littermates are available as control animals needed for proper study design.

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Headline

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 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 colony directly in our research facility. Animals of all age groups are typically available without any long delay. Non-transgenic littermates are available as control animals needed for proper study design.

We would be happy to test your compounds in this mouse model!

The most common readouts are:

Dendritic network break down and neuronal loss
Gliosis (astro- and activated microglia)
Looking for something else? Please contact us!

Alternative model

QPS Austria offers alternative models allowing the performance of the same type of studies also in every other commercially available mouse line, e.g. SOD1G93A(HI)

You might be also interested in these related topics

  • TDP in APP transgenic mouse model

 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.

SOD1-G93A TRANSGENIC MOUSE MODEL

SOD1-G93A mice express human SOD1 with the G93A mutation under control of the cistronic human SOD1 promotor. The Super Oxide Dismutase (SOD1) binds free copper and zinc ions and destroys free superoxide radicals in the body. Mutations in this gene have been linked to familial Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s disease). The SOD1-G93A mice show a phenotype similar to Amyotrophic Lateral Sclerosis in humans. They develop paralysis in one or more limbs within a few weeks of age.

These mice are a valuable tool to study the influence of new drugs on neuromuscular disorders such as Amyotrophic Lateral Sclerosis.

 

QPS Austria also offers research services with the SOD1 low copy number mouse model. Animals develop the same phenotype as the above described SOD1 high copy number mouse model, but disease onset is at about 6-7 months and thus extending the treatment window. Animals survive appr. 6 weeks after symptom onset.

TDP-43 TRANSGENIC MOUSE MODEL

TDP-43 related neurodegeneration has gained more and more attention during the last years. While TDP-43 is strongly related to sporadic and familial forms of Amyotrophic Lateral Sclerosis (ALS), intraneuronal pTDP-43 accumulation and aggregation is also related to Fronto-temporal Lobe Degeneration (FTLD-TDP or formerly FTLD-U) and was recently shown to be correlated to Alzheimer’s Disease (AD) pathology and Hippocampal Sclerosis.

TAR6/6 mice express human TAR DNA binding protein (TARDBP) under regulatory control of the neuron specific Thy1 promoter (Wils et al. 2010). Mice are bred on a C57BL/6 background. Homozygous mice die prematurely at 6 months and suffer from a severe ALS like motor phenotype. TAR6/6 mice are unable to fulfill the wire suspension task at an age of 6 weeks. This early disability is predictive for the homozygous genotype. TAR6/6 mice further develop deficits on the running wheel task, disturbed nest building, and altered anxiety levels. At approximately 3 months of age TAR6/6 mice display memory deficits in contextual fear conditioning.

All those phenotypical changes are accompanied by severe neurodegeneration seen in the brain, especially in thalamic neurons of TAR6/6 mice. Most central thalamic nuclei suffer from a severe break down of dendritic network, which is followed by neuronal loss and a strong local neuroinflammation. The latter as seen by astro- and microgliosis can also be found in the hypothalamus, the medulla oblongata and to a lower extent in spinal cord grey matter.

Hence these mice offer a unique opportunity to counteract TDP-43 related neurodegeneration in a fast and severe motor and memory phenotype model.

Figure 1: Wire hanging time of 6 weeks old TAR6/6 transgenic mice compared to non-transgenic littermates (ntg). A: tg N = 5; ntg N = 7 Mann Whitney test. Data are shown as mean±SEM. **p<0.01.

Image Link: http://qpsneuro.com/wp-content/uploads/TDP43-figure-wire-hanging-test-week-6-300×218.png

Figure 2: Latency to fall from the RotaRod in 6 weeks (A) and 14 to 17 weeks old TAR6/6 transgenic mice (B) compared to non-transgenic littermates (ntg). A: tg N = 5; ntg N = 7; B: tg N = 11-3; ntg N = 16-5. Unpaired t-test or Mann Whitney test depending on normal

Image Link: http://qpsneuro.com/wp-content/uploads/TDP43-figure-rota-rod-test.png

Figure 3: Time spent in the open arms of the EPM of 6 (A) and 18 weeks (B) old TAR6/6 transgenic mice compared to non-transgenic littermates (ntg). A: tg N = 5; ntg N = 6; B: tg N = 8; ntg N = 16. Data are shown as mean ±SEM. Data were analyzed by Mann Whitney test. ***p<0.001.

Image Link: http://qpsneuro.com/wp-content/uploads/TDP43-figure-elevated-plus-maze-test.png

Relevant Documents

ALZHEIMER’S DISEASE

QPS Neuropharmacology is experienced in generating, characterizing and maintaining of transgenic disease models and using them for drug testing projects for more than 15 years.

We are happy to receive any inquiry to elaborate the most efficient way, including behavioral, immunohistochemical, biochemical and molecular biological techniques, for the support of your drug development approach.

Our biobank can provide samples (brain tissue, CSF, etc.) of our animal models for analyses in your laboratory.

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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 Austria 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 x hQC transgenic Mouse Model

ApoB-100 transgenic Mouse Model

ApoB x APP transgenic Mouse Model

5xFAD transgenic Mouse Model

1 transgenic Mouse Model

Tg4-42 (TBA83) Mouse Model

Tg2576 Mouse Model

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!

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

 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.

AAPSL TRANSGENIC MOUSE MODEL

APPSL transgenic mice over-express human APP751SL under the control of the murine Thy-1 promoter. 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. Starting at 3 – 6 months APPSL mice develop plaques consisting of amyloid depositions 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). This model presents with an unchanged motor performance. The modifiability of several of these pathologies was already shown in a whole series of treatment studies (Windisch et al., 2013).

 

Figure 1: Assessment of spatial learning in the Morris water maze learning curves showing distance traversed and escape latencies during 4 testing days of 6 (A, D), 9 (B, E) and 12-month (C, F) old APPSL (blue) and WT (orange) animals. 6-month old APPSL n=19, WT n=21; 9-month old APPSL n=21, WT n=19; 12-month old APPSL n=13, WT n=22; Statistical analyses: Two-way-ANOVA with Bonferroni‘s post-test compared to WT. *p<0.05; **p<0.01; ***p<0.001.

Figure 2: Qualitative comparison of plaque pathology of APPSL transgenic mice at 3, 6 and 9 months of age. Tissue was labeled with antibody 6E10. Scalebar: 1mm

AAPS x hQC TRANSGENIC MOUSE MODEL

QPS 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.

ApoB-100 TRANSGENIC MOUSE MODEL

ApoB-100 mice were designed as a model of hyperlipidemia and atherosclerosis. Increasing evidence suggests that hypercholesterolemia and other vascular factors may contribute to the pathogenesis of late onset Alzheimer’s Disease (LOAD). ApoB is known as the primary apolipoprotein of cholesterol-carrying low-density lipoproteins (LDL) and triglyceride-rich very-low-density lipoproteins (VLDL). Atherosclerosis and AD patients share a very similar pathological plasma lipid profile, exhibiting increased levels of LDL along with decreased high-density lipoprotein (HDL) levels. Intriguingly, a post-mortem study of AD patients showed that LDL and ApoB levels positively correlate with brain Aβ42 levels.

ApoB-100 animals overexpress the entire 43 kb human apolipoprotein B-100 (ApoB-100) gene including its natural human promoter. 

ApoB-100 mice have:

  • Decreased learning and memory
  • Increased total cholesterol and triglycerides
  • Increased LDL but decreased HDL levels
  • Increased lipid peroxidation
  • Strong ApoB-100 accumulation at cerebral vessels
  • Increased Aβ1-38, 1-40 and 1-42 levels
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 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 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).

Additional readouts of ApoB x APP mice are:
•    LDL- and HDL- cholesterol levels
•    Cerebral accumulation of ApoB-100 in leptomeningeal vessels

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 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.

 

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.

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 mice were developed and characterized by Alexandru and colleagues.

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).

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).

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 Rota Rod 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).

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 dependent 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 and eventually to the final report is about 4 months.

QPS Austria maintains its own colony directly in our research facility. Animals are typically available without any long delay. 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
  • Prepulse Inhibition
  • Looking for something else? Please contact us!
Tg4-42 (TBA83) TRANSGENIC MOUSE MODEL

This 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.

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:

  • 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
Tg2576 TRANSGENIC MOUSE MODEL

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

TAU TRANSGENIC MOUSE MODELS

QPS Austria offers custom tailored study design for these models and we are flexible to accommodate to your special interest. We are also happy to advice 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 colony directly in our research facility. Animals of all age groups are typically available without any long delay. Compared to other tau transgenic mouse models, the TMHT line shows relevant features of tauopathies already at young age. This allows for extraordinarily fast turn-around times. Non-transgenic littermates are available as control animals needed for proper study design.

We would be happy to test your compounds in our tau transgenic mouse models!

The most common readouts are:

Memory (MWM)

Tau and tau phosphorylation (p181, p202, p231, p262, and p396) in brain extracts

Tau pathology evaluated by IHC with antibodies HT7 (human tau), Tau-5 (total tau), AT180, 9G3, AT8

Looking for something else? Please contact us!

Alternative models

QPS Austria offers alternative models allowing the performance of the same type of studies also in every other commercially available mouse line, e.g. P301L.

You might be also interested in these related topics

  • Tau surrounding plaques in the APP transgenic mouse model
  • Tau phosphorylation in hypothermia mouse model
  • Human tau overexpressing cell line
  • Tau and ptau in human CSF samples

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.

TMHT TRANSGENIC MOUSE MODEL

The TMHT (Thy-1 Mutated Human Tau) mouse was developed in-house and is exclusively available at QPS Austria. These animals represent a suitable model not only for Alzheimer’s disease but also for other Tauopathies such as Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and Niemann Pick’s disease.

Various compounds of different classes (among them also antibody treatments) were positively tested for their efficacy in the TMHT model. Published examples are the γ-secretase modulator CHF5074 (Lanzilotta 2010), sodium selenate (Corcoran et al., 2010) and grape-seed polyphenol extract (Wang et al., 2010).

 

TMHT mice express the longest human tau isoform Tau441 (2N4R) with two mutations, V337M and R406W, under regulatory control of the neuron specific murine Thy-1 promoter. Mice are bred in our facility on a C57BL/6 background. The human tau overexpression leads to high levels of soluble and sarcosyl insoluble tau in the brain with an age dependent increase (Figure 1).

 

Transgenic tau gets hyperphosphorylated at different disease relevant residues. Tau hyperphosphorylation is accompanied by a pronounced memory deficit. Already 5 months old TMHT animals demonstrate spatial learning deficits as shown by a significantly increased swim length and escape latency. Learning curves in the Morris water maze are by far not as steep as in non-transgenic littermates. (Figure 2)

 

Importantly, no motor deficits are observed for this model. Further, the TMHT mouse line resembles human AD tau pathology as evaluated by immunohistochemistry. Human tau accumulates mainly in neuronal somata. Especially in the amygdala an age-dependent increase of both ptau and human total tau levels is observed.

hTau TRANSGENIC MOUSE MODEL

hTau mice express human tau derived from a human PAC, H1 haplotype, known as 8c mice, while murine tau is knocked out by a targeted disruption of exon 1. Animals express all 6 human tau isoforms and present with accumulations of hyperphosphorylated tau, aggregated tau and PHFs.

Relevant Documents

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The γ-Secretase Modulator CHF5074 Reduces the Accumulation of Native Hyperphosphorylated Tau in a Transgenic Mouse Model of Alzheimer’s Disease

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AUTISM DISEASE

The cause of Autism Spectrum Disorder (ASD) as a complex developmental disorder with highly varying degrees is still under investigation. Research suggests that multiple factors, such as genetic vulnerability and environmental factors are involved in the development of the disorder. QPS Austria offers an extensive CRO service to test your compounds in a frequently used ASD mouse model.

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BTBR T+tf/J MOUSE MODEL

The cause of Autism Spectrum Disorder (ASD) as a complex developmental disorder with highly varying degrees is still under investigation. Research suggests that multiple factors, such as genetic vulnerability and environmental factors are involved in the development of the disorder. QPS Austria offers an extensive CRO service to test your compounds in a frequently used ASD mouse model.

The BTBR T+ tf/J mouse model is a suitable model not only for ASD but also for any other disorder characterized by social deficits.

BTBR T+ tf/J mice are commercially available and are the most widely used model for ASD research and related test substance analyses. Various compounds of different classes were positively tested for their efficacy in the BTBR T+ tf/J model. Recently published examples are the acetylcholinesterase inhibitor donepezil (Karvat & Kimchi, 2013), the noradrenergic reuptake inhibitor atomoxetine (Stapley et al., 2013) and the partial glycineB site agonist D-cycloserine, targeting the NMDA receptor (Burket et al., 2013).

BTBR T+ tf/J mice are an inbred strain completely missing the corpus callosum. Animals present a severely reduced hippocampal commissure. Behavioral analyses of BTBR T+ tf/J mice for motor deficits reveals highly significant reduced motor performance in the wire suspension test (Fig.1A) and nest building test (data not shown). Analysis of the autogrooming behavior shows that the number of grooming bouts are not altered between BTBR T+ tf/J and C57BL/6 mice, but that the mean duration of grooming bouts significantly increased in BTBR T+ tf/J mice (Fig.1B).

Furthermore, BTBR T+ tf/J mice present with an altered anxiety related behavior that was analyzed with the elevated plus maze test (Fig.2A). Analysis of BTBR T+ tf/J mice for cognitive deficits showed a significantly increased number of wrong choices in the two choice swim test suggesting, that animals have spatial learning deficits (Fig.2B).

Our results and that of others (McFarlane et al., 2008; Scattani et al., 2013) show that BTBR T+ tf/J mice display the most common symptoms of ASD, such as social behavior and interaction, exploration, anxiety and cognitive deficits, and are thus a valuable model for ASD research.

QPS Austria offers a 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 4 months. Animals will be purchased right after your order. Animals of all age groups are typically available without any delay. BTBR T+ tf/J mice show relevant features of ASD already at young age. This allows for extraordinarily fast turn-around times. Furthermore, C57BL/6 mice are available as control animals needed for proper study design.

We would be happy to test your compounds in our BTBR T+ tf/J inbred mouse model!

The most common readouts are:

Social approach and recognition
Learning and anxiety
AChe and CHAT levels
Looking for something else? Please contact us!

You might be also interested in these related topics:

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.

Relevant Documents

GAUCHER’S DISEASE

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4L/PS-NA TRANSGENIC MOUSE MODEL

4L/PS-NA mice express low levels of prosaposin and saposins, as well as β-glucosidase (GCase) with a point mutation at position V394L/V394L and model Gaucher disease, the most common lysosomal storage disease. The neuronal disease variant is characterized by aggregated protein accumulations in the brain and associated neurological manifestations.
Homozygous 4-24 weeks old 4L/PS-NA mice thus present with progressive α-synuclein aggregate accumulations in cortex, hippocampus, basal ganglia, brainstem and some cerebellar regions. Furthermore, 4L/PS-NA mice present a strong enlargement of leukocytes and macrophages in visceral organs like spleen, thymus, lung and liver as early as 5 weeks of age. With increasing age, 4L/PS-NA mice develop motor deficits and reduced muscle strength that is accompanied by strong neuroinflammation in the cortex and hippocampus, and thus exhibiting the neuronopathic phenotype of Gaucher disease.
QPS Austria is also ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory.

HUNTINGTON’S DISEASE

Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable at middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea. The disease is caused by an autosomal dominant mutation of the huntingtin gene.

The mutation of the huntingtin gene codes for a different form of the huntingtin protein, whose presence results in gradual damage of specific areas of the brain. Symptoms of the disease can vary between individuals and among affected members of the same family, but progress predictable for most individuals. The earliest symptoms are a general lack of coordination and an unsteady gait.

As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral and psychiatric problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into dementia.

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R6/2 TRANSGENIC MOUSE MODEL

R6/2 mice model human Huntington’s disease (HD) by expressing a portion of the human HD gene under human gene promoter elements (1 kb of 5 UTR sequence and exon 1 together with ~140 CAG repeats). Expression of this amino-terminal fragment of the huntingtin protein with its polyglutamine expansion is sufficient to reproduce the phenotype of human HD.

BACHD TRANSGENIC RAT MODEL

Huntington’s disease (HD) is an autosomal-dominantly inherited, fatal, neurodegenerative disorder. Patients present with motor dysfunction, psychiatric disturbances, cognitive impairments and metabolic abnormalities. The sole cause of developing HD is the expansion of an unstable repeat of CAG base triplets in the coding region of the Huntingtin gene, HTT. CAG repeat lengths of up to 34 are considered to be physiological, while more than 35 CAG repeats lead most likely to the development of HD. The age of disease onset correlates inversely with CAG repeat length and starts at the age of 40–50 years.

BACHD rats overexpress full-length human mutant HTT (mHTT) with 97 alternating CAA/CAG repeats on a bacterial artificial chromosome (BAC).

  • Heterozygous BACHD rats:
  • mHTT aggregates
  • Motor deficits
  • Reversal learning deficits
  • Reduced anxiety
  • Striatal alterations

QPS Austria is ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory.

Homozygous BACHD rats:

  • Homozygous BACHD rats present the same phenotype as heterozygous BACHD rats but with an earlier disease onset

NIEMANN-PICK DISEASE

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NPC1-/- MOUSE MODEL

Niemann-Pick C1 (NPC1), predominantly expressed in perisynaptic astrocytic glial cells (Patel et al., 1999), is involved in intracellular cholesterol trafficking (Peake et al., 2010). It plays an important role in glial vesicular trafficking, a process crucial for maintaining structural and functional integrity of nerve terminals (Patel et al., 1999).

Defects in NPC1 cause Niemann-Pick disease type C1, an inherited lysosomal storage disorder that affects the viscera and the central nervous system. The disease is caused by defective intracellular processing and transport of low-density lipoprotein derived cholesterol and it causes accumulation of cholesterol  in lysosomes, with delayed induction of cholesterol homeostatic reactions (Mattsson et al., 2012).

Interestingly, NPC disease shares similarities with Alzheimer’s disease (AD) showing progressive neurodegeneration, accumulation of amyloid-beta peptides, APP C-terminal fragments (Mattsson et al., 2012) and hyperphosphorylated tau (Ohm et al., 2003). The AD-like pathological features were identified both in the brains of NPC patients and NPC (NPC1-/-) mouse model (Mattsson et al., 2012).

Typical pathological features of Niemann-Pick disease:

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NPC1 TISSUE WEIGHTS
Tissue weight of livers and brains were evaluated in 7 weeks old NPC1-/- and wildtype animals. Liver weight in NPC1 knockout animals is about 1.5 times higher compared to wildtype animals (Fig. 1 left side). In contrast, brain weight is significantly decreased in NPC1-/- mice compared to corresponding littermates (Fig. 1 right side).
NPC1 TISSUE CHOLESTEROL LEVELS
Total and free cholesterol levels were assessed in livers and brains of 7 weeks old animals. While total (TC) and free (FC) liver cholesterol levels are about 5.5 times higher (Fig.2, left panel), brain cholesterol levels were similar in NPC1 knockout animals compared to wildtype littermates (Fig.2, right panel). Moreover, Filipin staining of brain lipids revealed enhanced lipid accumulation in the cerebellum and hippocampus of NPC1-/- animals (data not shown).
NPC1-/- PURKINJE CELL DEGENERATION
NPC1 knockout mice show a fast neuronal loss, especially Purkinje cells of the cerebellum are vastly affected (Fig. 3). Additionally to a decreased number of Purkinje cells, expression of APP in NPC1-/- mice is also altered in this cell type.
NPC1-/- NEUROINFLAMMATION
NPC1 knockout mice show enhanced neuroinflammation as analyzed by activated microglia and astrocytosis (Fig.4).
NPC1 MOTOR COORDINATION DEFICITS OVER AGE
RotaRod and gait analysis were used to assess motor coordination. At an age of 5 weeks, NPC-/- animals did not show any differences compared to wildtype animals in both RotaRod and Gait Analysis. However, 7 weeks old NPC-/- showed a significantly decreased latency to fall from the rod compared to 5 weeks old NPC-/- animals and 7 weeks old non-transgenic (ntg) littermates in the RotaRod, as well as increased time of step cycle in gait analysis compared to 7 weeks old ntg animals (Fig.5).

Relevant Documents

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Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease.

Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ, Neufeld EB, Patel RC, Brady RO, Patel YC, Pentchev PG, Ong WY. Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease. Proc Natl Acad Sci USA. 1999 Feb 16;96(4):1657-62.
h

Defective cholesterol trafficking in Niemann-Pick C- deficient cells.

Peake KB, Vance JE. Defective cholesterol trafficking in Niemann-Pick C- deficient cells. FEBS Lett. 2010 Jul 2;584(13):2731-9. doi:10.1016/j.febslet.2010.04.047. Epub 2010 Apr 21.
h

Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches.

Rosenbaum AI, Maxfield FR. Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J Neurochem. 2011 Mar;116(5):789-95. doi: 10.1111/j.1471-4159.2010.06976.x. Epub 2011 Jan 7.
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Amyloid-β metabolism in Niemann-Pick C disease models and patients.

Mattsson N, Olsson M, Gustavsson MK, Kosicek M, Malnar M, Månsson E, Blomqvist M, Gobom J, Andreasson U, Brinkmalm G, Vite C, Hecimovic S, Hastings C, Blennow K, Zetterberg H, Portelius E. Amyloid-β metabolism in Niemann-Pick C disease models and patients. Metab Brain Dis. 2012 Dec;27(4):573-85. doi:10.1007/s11011-012-9332-8. Epub 2012 Sep 1.

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