Caracterización comparativa del aprendizaje y la memoria en ratas añosas de genotipo salvaje y transgénicas modelo de la enfermedad de Alzheimer
The transgenic rat model for Alzheimer disease McGill-R-Thy1 bears the transgene of human amyloid precursor protein (APP) with two familial Alzheimer?s disease (AD) mutations Swedish and Indiana. This animal model presents early hippocampal and cortical intracellular A? peptides accumulation. Homozy...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_5915 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_5915.dir/5915.PDF |
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| Sumario: | The transgenic rat model for Alzheimer disease McGill-R-Thy1 bears the transgene of human amyloid precursor protein (APP) with two familial Alzheimer?s disease (AD) mutations Swedish and Indiana. This animal model presents early hippocampal and cortical intracellular A? peptides accumulation. Homozygous animals exhibit intracellular A? oligomers from the first week of life and extracellular amyloid plaques deposit from 6 months of age. 13 months homozygous animals showed deficits in the Morris Water Maze, fear conditioning and new object recognition (NOR), whereas 3 months rats showed deficits in the new objects location (NOL). Instead, hemizygous rats present features that would correspond with an earlier step of AD when there is no amyloid plaques accumulation yet. 3 months hemizigous rats showed deficits in the water maze, while 13 months rats showed deficits in NOR and fear memory.\nMany investigations have shown that inflammation is involved in the physiopathology of AD. Retrospective and prospective clinical studies found that anti-inflammatory drugs decreased future AD risk. Furthermore, animal models of AD found a positive correlation between inflammation and A? peptide species accumulation and increase behavioral deficits.\nWe characterized cognitive features of hemizygous TG in parallel with their wild genotype littermates (WT) to discriminate putative age deficits from those due to intracellular A? oligomers. We assessed 13 month old TG and WT rats habituation to an open field (OF), performance in a step-through inhibitory avoidance (ST-IA), NOL and NOR tasks.\nTo study possible inflammation involvement in our animal model we performed immunolabeling against Iba-1 and GFAP in the CA1 region of the hippocampus to evaluate the percentage of area cover by microglia and astrocytes cells respectively. To estimate if hippocampal neurons presented signs of degeneration we used antibodies directed against NeuN, that usually located in the nucleus but it is distributed to the cytoplasm in case of cellular stress.\n6\nThere were no differences between WT and TG rats in OF total exploration parameters, showing that both were able to habituate to the environment for the ST and able to express the memory in the LT (24 h later). TG seemed to be unable to learn the ST-IA task, while WT rats performed well. Neither Wts aged rats nor TGs seemed to discriminate NOL at variance with younger animals, that were able to learn and form a memory. WT performed well in the ST and LT for NOR, while TG only showed ST memory for NOR. Unexpectedly, we found astrocyte atrophy in TG rats compared to WT rats whereas the covered area by microglia cells was similar in both animals groups. TG animals showed increased NeuN redistribution from the nucleus to the cytoplasm indicating neurodegeneration.\nIn conclusion, these degenerative changes could be consecuence of different etiologies as the A?-oligomer attacks to the sinapses and neurons or the possible astroglia atrophy decreasing neuronal and sinapses funcion. It could be also consequence of the inespecific inflammation induced by A? species, including A? oligomers. These results suggest that the observed patology in the hippocampus can directly relate tio the memory deficits, particularly in the lon term memory, both in the NOR and ST-IA. |
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