A Research on Alzheimer’s Disease on Mouse Model

In the paper by Spires et al. they state that in transgenic mice, mutations in presenilin 1 (PS1) gene would lead to a high accumulation of AB1-42 peptide, however mals did not have the plaque formations or any characteristic neuronal behaviors. In another paper by Schaeffer et al. they state that senile plaques are mainly derived from the AB peptide, which are themselves derived from the APP protein precursor. In APP mutants, there is an overexpression of the APP human transgene, where the specimen developed some senile plaques that were mainly from the accumulation of AB1-42, as well as neuronal loss and severe neuronal behavior changes? In the doubly transgenic APP/PS1 mice, it was said that there were a large accumulation of the AB protein that promoted the development of senile plaques, especially in the cerebral cortex and the hippocampus.

From these findings, it can be hypothesized that from the slides, slide C (containing no plaques) could be classified as the PS1-Tg mutant due to its lack of senile plaques. For slide B, since it had a relatively small amount (proven to be statistically significant) of plaques seen compared to slide D, we could classify as being the APP-Tg mutant. Finally, slide D, which contained a statistically significant amount of plaques in the hippocampus and cerebral cortex, could be matched with the literature and said to be the doubly transgenic PS1XAPP-Tg mutant, due to its large accumulation and location of senile plaques. In these mice, they would expected to have a great loss of memory as well as attention and awareness, due to the main parts of the brain (hippocampus and cerebral cortex) being the major areas of plaque formation.

The use of transgenes mainly affects the pathway APP is processed, where instead of following the neurotropic alpha-secretase pathway of processing, more of it is directed towards the neurotoxic beta-secretase pathway, where gene products such as AB1-42 are made, resulting in the accumulation of senile plaques. There were no pyknotic nuclei (damaged nuclei of cell undergoing apoptosis) observed in the samples, which could explain a factor that perhaps human transgenes are not 100% effective in another host organism.

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Another mouse model used widely in Alzheimer's research is the Tg2576 mutant mice, which also has an overexpression of a human APP transgene?. In this mouse model, there was an extremely early onset of AB1-40 and AB1-42 accumulation, which gave plaques that resembled closely to that seen in Alzheimer's disease?. Signs of behavior atrophy were also seen very early, where mostly were due to neuronal loss in the hippocampus and spine density?. Unlike with the CRND8 APP-Tg model, there are much greater of familiar Alzheimer's, as well as a much slower accumulation of plaque (18 months with Tg2576 vs. 3 months with CRND8)”. The timing and duration of the plaque formation, as well as the onset of behavior effects of the Tg2576 transgenic mutant follows the human Alzheimer's disease much more closely, which is why it is a better model and also why it has been used more widely than the CRND8 APP-Tg mutant?.

Using a transgenic mouse model and yield a lot of errors, such as the difficulty to replicate an experiment in a transgenic mouse". Since each mice mutant is genetically different, expressing a human transgene in to a mouse would perhaps yield different results each time, or have different phenotype effects that would not be expected. In addition, human genetics and mouse genetics might yield homologues, however the overall system and genetic components are different and by using a mouse model, we can perhaps understand and characterize the disease better, however to actually find a cure or model it in humans could be a lot more complicated than in mice. The genetics of the mice, as well as the environment used to conduct the experiment would also have a major effect on the results of using transgenic mice for neurodegenerative diseases, which is something that needs to be carefully controlled“.

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