TBI-INDUCED FORMATION OF TOXIC TAU AND ITS BIOCHEMICAL SIMILARITIES TO TAU IN AD BRAINS

Background: The proposed research project is aligned against the Convergence Science Research Award (CRSA) overarching challenge of addressing the paucity of research resources to examine the interrelationship between traumatic brain injury (TBI) and subsequent Alzheimer's disease (AD) for military Veterans/other individuals affected by TBI. Specifically, this project aligns with the CRSA 'pathology of tau' focus area by seeking to unravel the basic pathological mechanisms of tau associated with TBI and AD. The long-term goal of this work is alleviate the burdens that TBI and AD impose on caregivers and affected individuals to by providing the knowledge necessary to develop effective preventative or therapeutic strategies for these conditions.A number of similarities exist between AD and neurodegeneration associated with TBI, which suggests that common molecular mechanisms contribute to both of these disorders. Among these is the characteristic presence of aggregates of hyperphosphorylated tau, which are a histological hallmark of both AD and TBI-associated neurodegeneration. Soluble toxic oligomers of tau impair behavior and synaptic plasticity as well as seed the spread of this pathology in animal models. Our preliminary data show that tau purified from human AD brains produces cognitive and electrophysiological impairments in mice, while tau prepared in parallel from the brain of healthy control individuals produced an impairment only at much higher concentrations. Using our mouse model of blast-induced TBI, we found that tau purified from these animals but not sham-injured animals produces similar cognitive and electrophysiological impairments. In addition, we found that transgenic manipulation of the activity of the tau phosphatase PP2A alters the sensitivity behavioral impairments caused by oligomeric preparations of recombinant tau. In the proposed research project, we will build on these preliminary data to explore the following hypothesis and specific aims.Hypothesis: We hypothesize that blast-induced TBI and Alzheimer's disease lead to similar biochemical changes in tau that increase its toxicity and contribute to cognitive and electrophysiological impairments.Specific Aims: (1) We will test the hypothesis that blast-induced TBI leads to the production of a toxic form of tau that contributes to cognitive and electrophysiological impairments. (2) We will test the hypothesis that the formation of soluble tau aggregates contributes to cognitive impairments associated with both blast-exposure and AD. (3) We will test the hypothesis that an increase in tau phosphorylation contributes to cognitive impairments associated with both blast-exposure and AD.Research Strategy: In Aim 1, we will purify tau from shockwave-exposed and sham-exposed mice, and test its ability to impair cognitive performance and synaptic plasticity through behavioral tests of mice infused with these preparations or through electrophysiological recordings in acute hippocampal slice preparations. We will then confirm the tau dependence of the activity in these preparations by tau immunodepletion and by testing preparations from shockwave-exposed tau knockout mice. We will also determine the dose dependence of these behavioral and electrophysiological impairments. In Aim 2, we will compare the degree and type of tau aggregation in homogenates prepared from shockwave vs. sham-exposed mouse brains and AD vs. healthy control human brains, and test the dependence of the toxicity in these preparations on the presence of these oligomers by biochemical de-oligomerization and oligomer-specific immunodepletion. In Aim 3, we will compare the degree and type of tau phosphorylation in homogenates prepared from shockwave vs. sham-exposed mouse brains and AD vs. healthy control human brains using mass spectrometry and phospho-tau specific western blotting. We will then explore the possibility that response to or production of toxic tau could be affected by the activity of the tau phosphatase, PP2A.