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Transgenic Rat Model (transgenic + rat_model)
Selected AbstractsTruncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle loadEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2008Peter Koson Abstract We have previously demonstrated in a transgenic rat model of tauopathy that human misfolded truncated tau derived from Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. We employed this model to investigate the impact of truncated tau expression levels on life span, neuronal loss and the final load of neurofibrillary tangles (NFTs) in transgenic rats. Two independent transgenic lines (SHR72, SHR318), that display different expression levels of truncated tau, were utilized in this study. We found that transgene expression levels in the brain of SHR72 rats were 44% higher than in SHR318 rats and that truncated tau protein levels determined the survival rate of transgenic rats. The line with higher expression levels of truncated tau (SHR72) showed decreased median survival (222.5 days) when compared with the line with lower expression (SHR318; 294.5 days). Interestingly, NFT loads (total NFT/total neurons) were very similar in terminal stages of disease in both transgenic lines (SHR72 , 10.9%; SHR318 , 11.6%), despite significantly different expression levels of truncated tau. Moreover, mean neuron numbers in the hippocampus (CA1,3) and brain stem (gigantocellular reticular nucleus) in the two transgenic rat strains in the terminal stages of disease were similar, and did not differ significantly from those observed in age-matched non-transgenic controls. These findings suggest that the expression levels of misfolded truncated tau determine the life span in a transgenic rat model of tauopathy without causing neuronal loss or correlating with terminal NFT load. [source] Gene Transfer Strategies for the PhysiologistEXPERIMENTAL PHYSIOLOGY, Issue 6 2000Liang-Fong Wong Foreign genes can be introduced into whole animals using methods of germline transgenesis and somatic gene delivery. While germline transgenesis can generate useful animal models for genetic studies, it can be costly, time-consuming and requires the use of a large number of animals. An alternative means of gene transfer is to deliver genes to somatic cells using non-viral and viral technologies. Non-viral methods such as naked DNA injection, electroporation and liposome/cation lipid-mediated gene transfer are relatively inefficient. In contrast, viruses are effective vehicles that carry foreign genes into a cell rapidly and efficiently. Here we illustrate the usefulness of adenoviral vectors to express a potent and specific inhibitor of cAMP-dependent protein kinase (PKA) to study the role of cyclic 3,,5,-cyclic AMP (cAMP) in the osmotic regulation of the vasopressin gene in a transgenic rat model. The ability to modify endogenous systems within specific cells in a whole animal model allows gene effects to be studied with physiological relevance. The combination of molecular biology and integrative physiology is a powerful application that can aid in the elucidation of how gene function can translate into complex systems in an organism [source] From HLA-B27 to spondyloarthritis: a journey through the ERIMMUNOLOGICAL REVIEWS, Issue 1 2010Robert A. Colbert Summary:, Almost four decades of research into the role of human leukocyte antigen-B27 (HLA-B27) in susceptibility to spondyloarthritis has yet to yield a convincing answer. New results from an HLA-B27 transgenic rat model now demonstrate quite convincingly that CD8+ T cells are not required for the inflammatory phenotype. Discoveries that the HLA-B27 heavy chain has a tendency to misfold during the assembly of class I complexes in the endoplasmic reticulum (ER) and to form aberrant disulfide-linked dimers after transport to the cell surface have forced the generation of new ideas about its role in disease pathogenesis. In transgenic rats, HLA-B27 misfolding generates ER stress and leads to activation of the unfolded protein response, which dramatically enhances the production of interleukin-23 (IL-23) in response to pattern recognition receptor agonists. These findings have led to the discovery of striking T-helper 17 cell activation and expansion in this animal model, consistent with results emerging from humans with spondyloarthritis and the discovery of IL23R as an additional susceptibility gene for ankylosing spondylitis. Together, these results suggest a novel link between HLA-B27 and the T-helper 17 axis through the consequences of protein misfolding and open new avenues of investigation as well as identifying new targets for therapeutic intervention in this group of diseases. [source] Early Electrophysiological Changes In Transgenic Rat Model Of Charcot-Marie-ToothJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2001M Grandis Recently, a reliable transgenic rat model of human Charcot-Marie-Tooth type 1 A has been developed. So far, neurophysiological studies have been performed only in advanced stages of rat disease. Moreover, axonal involvement, which is known to occur in human CMT1A, has never been observed in this rat model. Affected rats show overexpression of Peripheral Myelin Protein (PMP-22) and a peripheral hypomyelinating neuropathy. We perfomed an electrophysiological study in two heterozygous PMP-22 transgenic rats and in one normal control, matched for age (3 weeks) and weight (average: 60 g). Recordings were performed in vivo by stimulating the sciatic nerve at both sciatic notch and ankle sites and recording the Hoffman reflex and direct muscle responses (CMAP). The H-reflex related SNCV and MNCV were calculated by measuring the distance between the sciatic notch and the ankle sites and the respective latencies. The two transgenic rats showed different levels of PMP-22 overexpression, as judged by quantitative PCR. The rat with a lower PMP-22 gene level showed a 30% reduction of MNCV compared to the normal control, while SNCV was not reduced. The CMAP was sized approximately 45% of the normal rat while the ratio between H wave amplitude and CMAP was 30% of the normal, the H wave amplitude being more affected than the CMAP. The action potentials in the rat with a higher transgene level were not recordable. Our data demonstrate that slowing of MNCV is an early finding in the CMT1A rat model. The marked reduction of H wave amplitude in front of a normal SNCV suggests a possible early axonal damage of sensory fibers. The entity of electrophysiological compromission positively correlated with the number of copies for PMP-22 gene. All together these considerations prove the sensitivity of this method, however further studies are needed to confirm these results and to prove that this model may be suitable to investigate the effects of therapeutic approaches. [source] Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathyANNALS OF NEUROLOGY, Issue 1 2007Gerd Meyer zu Horste MD Objective Charcot,Marie,Tooth disease (CMT) is the most common inherited neuropathy, and a duplication of the Pmp22 gene causes the most frequent subform CMT1A. Using a transgenic rat model of CMT1A, we tested the hypothesis that long-term treatment with anti-progesterone (Onapristone) reduces Pmp22 overexpression and improves CMT disease phenotype of older animals, thereby extending a previous proof-of-concept observation in a more clinically relevant setting. Methods We applied placebo-controlled progesterone-antagonist therapy to CMT rats for 5 months and performed grip-strength analysis to assess the motor phenotype. Quantitative Pmp22 RT-PCR and complete histological analysis of peripheral nerves and skin biopsies were performed. Results Anti-progesterone therapy significantly increased muscle strength and muscle mass of CMT rats and reduced the performance difference to wildtype rats by about 50%. Physical improvements can be explained by the prevention of axon loss. Surprisingly, the effects of anti-progesterone were not reflected by improved myelin sheath thickness. Electrophysiology confirmed unaltered NCV, but less reduced CMAP recordings in the treatment group. Moreover, the reduction of Pmp22 mRNA, as quantified in cutaneous nerves, correlated with the clinical phenotype at later stages. Interpretation Progesterone-antagonist treatment. Pmp22 overexpression to a degree at which the axonal support function of Schwann cells is better maintained than myelination. This suggests that axonal loss in CMT1A is not caused by demyelination, but rather by a Schwann cell defect that has been partially uncoupled by anti-progesterone treatment. Pmp22 expression analysis in skin may provide a prognostic marker for disease severity and for monitoring future clinical trials. Ann Neurol 2007;61:61,72 [source] | |||||||||||||