HOME > Products and Services >Non-Clinical Study Service using Genetically Engineered Mouse Models

Non-Clinical Study Service using Genetically Engineered Mouse Models

Topics/Campaign Information

  • 2017/09/14
    Open the pages for Non-Clinical Study Service using Genetically Engineered Mouse Models

Non-Clinical Study Service using Genetically Engineered Mouse Models

Trans Genic group offers the non-clinical study service using genetically engineered mouse models which were established in various research institutes through licensing agreement.

Lineup of Non-Clinical Study


Disease Genetically Engineered Mouse Models
Alzheimer’s disease APPosk-Tg mouse(Mouse prion promoter – Human APP E693Δ)
Neuropsychiatric disorders ProBDNF KI mouse(proBDNF R125M/R127L knock-in)
Dementia SJLB mouse (Mouse prion promoter – Human TAU N279K)

※Prices vary depending on the study plan. Please contact us.
* Behavior studies are performed in New Drug Research Center, Inc in Trans Genic group.

Back to Top

Alzheimer’s disease research model

Alzheimer’s disease research model Alzheimer’s disease and the amyloid hypothesis
Alzheimer’s disease (“AD”) is a progressive neurodegenerative disease accompanied by the decline in cognitive function. The pathological change in brain includes the accumulation of insoluble aggregate consisting of amyloid β (“Aβ”), called senile plaque, the accumulation of insoluble aggregate
consisting of TAU protein, called neurofibrillary tangle (“NFT”), and brain atrophy.
One of the hypothesis which explain ADpathogenesis is “Amyloid hypothesis” as below:

  • 1.Aβ forms soluble aggregate (Aβ oligomer) and insoluble aggregate (Aβ fibril).
  • 2.Aβ aggregates induce hyperphophorylation and auto-aggregation of TAU protein, forming abnormal aggregated TAU, NFT.
  • 3.NFT induces neuronal cell death.
  • 4.Brain atrophy progresses and cognitive impairment

Oligomer hypothesis and Osaka mutation
In the early amyloid hypothesis, it was considered that neuronal cell death induced by Aβ fibril (insoluble aggregate in senile plaque) causes cognitive decline. However, since Aβ level necessary for neuronal cell death is too high compared with the physiological level in vivo, and also severity of AD patients does not correlate with the amount of Aβ fibril in the brain, the existence of toxic substance other than Aβ fibril was suggested. Consequently, “Oligomer hypothesis”, in which Aβ oligomer leading synaptic dysfunction in physiological concentration might be important for AD development, was advocated. However, because both Aβ oligomer and Aβ fibril exist in the brain of AD patients, it was difficult to determine which form of Aβ contributes to AD pathogenesis.
he research group of Dr. Takami Tomiyama and Dr. Hiroshi Mori (Osaka City University) identified the novel gene mutation from a familial AD case in 2008. The mutation (APPosk, E693Δ) discovered was one amino acid deletion in amyloid precursor protein (“APP”) gene. Aβ peptide derived from APPosk, which lacks glutamate at position 22 (Aβ E22Δ), shows unique property of enhanced oligomerization but no fibrillization. Senile plaque was not detected in the brain of AD with APPosk mutation. The discovery of this mutation proved for the first time that AD develops by Aβ oligomer alone.

APPosk-Tg mouse
Average±SE.*p<0.05,** p<0.01 t-test

APPosk-Tg mouse
APPosk-Tg mice express human APPosk mutant protein in the brain. APPosk-Tg mice develop the accumulation of Aβ oligomer accompanied by aging, however, there is no senile plaque observed even at 24 months of age. On the other hand, various AD symptoms including synaptic loss, hyperphosphorylation of TAU protein, activation of glial cells, and neuronal cell death are observed in this mouse line. From these results, APPosk-Tg mice are considered to be the mouse model supporting “oligomer hypothesis”, and also helpful for the research of AD pathogenesis by Aβ oligomer, therapeutic development, and drug discovery.

< References >
■ Tomiyama T., Nagata T., Shimada H., Teraoka R., Fukushima A., Kanemitsu H., Takuma H., Kuwano R., Imagawa M., Ataka S., Wada Y., Yoshioka E., Nishizaki T., Watanabe Y. and Mori H. A new amyloid β variant favoring oligomerization in Alzheimer's-type dementia. Ann. Neurol. 63, 377-387 (2008).
■ omiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi, K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., Nishitsuji, K., Ito, K., Shimada, H., Lambert, M.P., Klein, W.L. and Mori, H.
A mouse model of amyloid β oligomers: Their contribution to synaptic alteration, abnormal Tau phosphorylation, glial activation, and neuronal loss in vivo. J. Neurosci. 30, 4845-4856 (2010).
■ Umeda T., Ono K., Sakai A., Yamashita M., Mizuguchi M, Klein W.L., Yamada M., Mori H. and Tomiyama T. Rifampicin is a candidate preventive medicine against amyloid β and tau oligomers.Brain 139, 1568-1586 (2016).

< Patent >
■ WO/2006/038729 “Mutated Amyloid Protein”

Back to Top

Neuropsychiatric disorder research model

BDNF and neuropsychiatric disorder BDNF and neuropsychiatric disorder
Brain derived neurotrophic factor (BDNF) is one of the neurotrophic factor, which has received the attention to be a substance relevant to various neuropsychiatric disorders such as depression in recent years. It is shown that BDNF is important for the formation, development, and maintenance of neural network, synaptic plasticity, as well as memory formation and learning. Mature BDNF is produced by the cleavage of proBDNF, precursor of BDNF. Mature BDNF binds to tyrosine kinase receptor (TrkB), and induces cell survival, cell differentiation and synaptogenesis. On the other hand, proBDNF binds to p75NTR receptor, and induces apoptosis and suppression of neurite elongation.

proBDNF KI mouse proBDNF KI mouse
Dr. Masami Kojima (the National Institute of Advanced Industrial Science and Technology) considered that impaired processing of proBDNF and deficient secretion might be involved in neuropsychiatric disorder including depression, and generated the knock-in mice in which mutation to suppress proBDNF processing is introduced. This knock-in mouse exhibits prolonged immobility time in the tail suspension test. ProBDNF knock-in mouse is valuable for the study of neuropsychiatric disorder including dementia, and contributes to the therapeutic development and drug discovery.

< References >
■ Mizui, T., Ishikawa, Y., Kumonogoh, H. and Kojima, M. Neurobiological actions by three distinct subtypes of brain-derived neurotrophic factor: Multi-ligand model of growth factor signaling.Phamacol. Res. 105, 93-98 (2016 review).
■ Mizui, T., Ishikawa, Y., Kumanogoh, H., Lume, M., Matsumoto, T., Hara, T., Yamawaki, S., Takahashi, M., Shiosaka, S., Itami, C., Uegaki, K., Saarma, M. and Kojima, M. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met.Pro. Nat. Aca. Sci. 112, E3067-3074 (2015).
Koshimizu, H., Hazama, S., Hara, T., Ogura, A. and Kojima, M. Distinct signaling pathways of precursor BDNF and mature BDNF in cultured cerebellar granule neurons.Neurosci. Letters 473, 229-232 (2010).
■ Koshimizu, H., Kiyosue, K., Hara, T., Hazama, S., Suzuki, S., Uegaki, K., Nagappan, G., Zaitsev, E., Hirokawa, T., Tatsu, T., Ogura, A., Lu, B. and Kojima, M. Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival.Mol. Brain 2, 27 (2009).

< Patent >
■ JP5414012B2 “Mutant BDNF gene-introduced knock-in mice”

Back to Top

Dementia research model


Dementia and TAU
There are many kinds of dementia such as AD, and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is known as an autosomal dominant disease. The signs and symptoms such as motion-impairment and cognitive dysfunction usually become noticeable in a person’s forties to sixties, and after a certain period, affected individuals may develop serious dementia. It is known that FTDP-17 is caused by the abnormality of TAU protein. Abnormal accumulation of TAU protein is considered to be directly associated with neural death, and the cause of AD. Some genetic mutations on TAU gene are already reported, including N279K mutation. This is the point mutation causing amino-acid replacement.

SJLB mouse SJLB mouse
SJLB mice express TAU protein with N279K mutation in the brain. SJLB mice exhibit the impairment of spatial ability and risk avoiding ability, therefore, are considered to be useful as the mice model of cognitive impairment to investigate the treatment method and therapeutic agents targeting TAU protein.
As a control mouse, UBJAP mouse which expresses human wild-type TAU is available.

< References >
■ Taniguchi, T., Doe, N., Matsuyama, S., Kitamura, Y., Mori, H., Saito, N. and Tanaka, C.Transgenic mice expressing mutant (N279K) human tau show mutation dependent cognitive deficits without neurofibllary tangle formation. FEBS letters 579, 5704-5712 (2005).

< Patent >
■ JP2011043428A “Inspection method of Parkinsonism using non-human animal model”

Back to Top
  • Press Release
Contact us/Products&ServicesE-mail
  • Reproductive Technology Training
Back to Top