An investigation of the effects of the transcription factor PAX6 in an Alzheimer's disease mouse model (CRND8)

Abstract

Alzheimer’s disease is the most common form of dementia, a debilitating neurodegenerative disease which affects the creation and retention of memories. It affects millions of people across the world, and despite its prevalence an effective treatment or therapy has yet to be discovered. To gain a better understanding of the disease we have investigated a potential candidate gene in the pathway of Alzheimer’s disease, paired homeobox 6 (PAX6), and its role in the mouse model TgCRND8. PAX6 is a developmental gene, necessary for normal development of the eye and several organs in the body. However, it was found to be elevated in Alzheimer’s disease patients, and is a potential candidate gene for an investigation. TgCRND8 mice are a transgenic strain of mice with a double mutation to produce human amyloid protein and convert it in high levels of amyloid-beta, forming plaques similar to those seen in human patients. By utilizing mice brains of different ages and therefore different stages of amyloid plaque development, we were able to visualize the change and increase of PAX6 protein levels in the TgCRND8 mice over time by counting PAX6 containing neuronal cells. In addition to the visualization of PAX6 within a transgenic mouse model, in vitro investigations on the downstream pathways of PAX6 were also performed, specifically regarding the effects on glycogen synthase kinase 3-beta (GSK3β) and its effect on the hyperphosphorylation of tau protein. As the hyperphosphorylation of tau protein has been hypothesized to not only contribute to but also be a cause of Alzheimer’s disease, this study focused on the effects of knocking down PAX6 in vitro on wild-type primary cortical neurons. It was found that there is a dramatic increase in the levels of PAX6 in an in vitro model of Alzheimer’s disease as well as an in vivo model of Alzheimer’s disease, the TgCRND8 mice. By investigating the role that PAX6 plays on the progression of Alzheimer’s disease as well as the localization of the protein in the neuronal cells of a transgenic mouse model, we hope to contribute to a better understanding of the complex causes and pathways of Alzheimer’s disease.