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.
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 distribution. Data are shown as mean±SEM. *p<0.05; ***p<0.001.
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.
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:
• Motor behavior (RotaRod, Beam Walk, Wire Hanging, Nest Building)
• Memory (CFC)
• TARDBP expression, pTDP-43
• Dendritic network break down and neuronal loss
• Gliosis (astro- and activated microglia)
• Looking for something else? Please contact us!
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.
We are happy to receive your inquiry.
Kovacs GG, Milenkovic I, Wöhrer A, Höftberger R, Gelpi E, Haberler C, Hönigschnabl S, Reiner-Concin A, Heinzl H, Jungwirth S, Krampla W, Fischer P, Budka H.; Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol. 2013 Sep;126(3):365-84. doi: 10.1007/s00401-013-1157-y. Epub 2013 Jul 31.
Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I, Smits V, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S. ; TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3858-63. doi: 10.1073/pnas.0912417107. Epub 2010 Feb 3.
Janssens J, Wils H, Kleinberger G, Joris G, Cuijt I, Ceuterick-de Groote C, Van Broeckhoven C, Kumar-Singh S.: Overexpression of ALS-associated p.M337V human TDP-43 in mice worsens disease features compared to wild-type human TDP-43 mice. Mol Neurobiol. 2013 Aug;48(1):22-35. doi: 10.1007/s12035-013-8427-5. Epub 2013 Mar 10.