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

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Columbia University New York United States

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The focus of our studies is to test the effect of genetic manipulations targeting tau phosphatase, PP2A, on behavioral impairments resulting from shockwave exposure, and to compare those results with the effects of the same manipulations on the sensitivity to Alzheimers disease AD - like impairments caused by acute A beta exposure. The principal motivation behind this approach is the observation that hyperphosphorylated tau is a common feature of multiple neurodegenerative conditions including AD and traumatic brain injury TBI -associated degeneration. We previously found that the two novel lines of transgenic Tg mice altering PP2A activity, modify sensitivity to A beta-induced electrophysiological and behavioral impairments, and our hypothesis is that they exert similar effects on shockwave-induced impairments. This effort has required a substantial investment in developing equipment and protocols for exposing mice to a range of shockwave exposure conditions that mimic militarily relevant exposures. We found changes in phospho-tau at 1 and 24 hrs post-injury. Behavioral analysis of the blast mice revealed changes in exploratory behavior and spatial memory which were not affected by PP2A modulation. These changes were associated with eye damage interfering with interpretation of behavioral results. However, given that we also found that blast causes tau protein changes reducing memory in normal mice, when we exposed our Tg mice to tau, we demonstrated modulation of memory loss by PP2A, confirming our initial hypothesis that therapies acting onto PP2A might be beneficial in TBI and AD.

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Technical Report,30 Sep 2012,29 Mar 2015



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Approved For Public Release;

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