Role of PP2A Methylation in Susceptibility and Resistance to TBI and AD-Induced Neurodegeneration.

摘要

The goal of the current study is to identify the molecular mechanisms that contribute to TBI or AD-related impairment so that this information can then be used to identify at-risk individuals and develop effective therapeutic approaches. Specifically we will test the hypothesis that level of protein phosphatase 2A (PP2A) methylation affects sensitivity to behavioral impairments resulting traumatic brain injury caused by shockwave exposure. The primary bases for this hypothesis are the observations that 1) aggregates of hyperphosphorylated tau are a common feature of multiple neurodegenerative conditions including Alzheimer's disease and traumatic brain injury-associated degeneration, and 2) that PP2A is the principal tau phosphatase. To test this hypothesis, we generated two lines of transgenic mice, one that over expresses the PP2A methylesterase, PME, and a second that over expresses the PP2A methyltransferase, LCMT. In previous work we found that transgenic PME over expression sensitized animals to electrophysiological and behavioral impairments caused by exogenous beta-amyloid exposure and that LCMT over expression protected animals from these impairments. Our prediction is that over expression of these transgenes will exert similar effects with respect to shockwave-induced impairments. In the past year of the project, we identified shockwave exposure conditions that reliably elicit acute increases in tau phosphorylation in mice, and assessed the effect of PME over expression on these increases. We also identified shockwave-induced behavioral impairments in these animals and similarly assessed the effect of PME over expression on these impairments. We also conducted a preliminary histological analysis of eyes from shockwave-exposed mice that identified shockwave related tissue damage at 24 days after injury. Additional, planned behavioral and histological analyses are ongoing that will allow us to complete our test of the hypothesis and provide n