TBI-Induced Formation of Toxic Tau and Its Biochemical Similarities to Tau in AD Brains

The long-term goal of this work is to alleviate the burdens that traumatic brain injury (TBI) and Alzheimer's disease (AD) impose on caregivers and affected individuals by providing the knowledge necessary to develop effective preventative or therapeutic strategies for these conditions.

TBI has been considered the signature injury of US military operations in Iraq and Afghanistan due primarily to the high incidence of survivable exposure to improvised explosive devices (IEDs) experienced in these conflicts, and AD represents a major public health concern, affecting 1 in 9 older Americans with numbers expected to increase as the population ages. TBI both increases the risk of AD and can also lead to a related neurodegenerative condition characterized by cognitive and behavioral symptoms similar to those found in Alzheimer's patients. On the histological level, AD and TBI-associated neurodegeneration are characterized by abnormal aggregates of the endogenous protein tau, suggesting that tau may play role in both of these conditions. In the proposed research project, we will explore the hypothesis that similar biochemical modifications of tau occur in TBI and AD brains that increase its toxicity and contribute to impairment of cognition and cell to cell communication. By understanding the molecular processes that underlie these disorders, we ultimately hope to be able to design interventions that prevent, halt, or reverse them.

In preliminary experiments using biochemical methods to isolate tau and behavioral assays as well as tests of cellular communication in mouse models, we found that tau from human AD brains and mouse brains subjected to TBI exhibit increased toxicity. We also found that genetic manipulation of the activity of an enzyme that biochemically modifies tau (protein phosphatase 2A) alters the sensitivity of these animals to toxic aggregates of tau. In the experiments outlined in this proposal, we will use similar strategies together with advanced biochemical methods, including shotgun proteomics and mass spectrometry, as well as novel reagents, including tau oligomer specific antibodies, to: (1) Validate our preliminary observations that blast-induced TBI leads to the production of a toxic form of tau capable of producing impairment of cognition and cell to cell communication. (2) Compare the type and degree of tau aggregation in human AD and mouse TBI brains and test our hypothesis that the presence of soluble tau aggregates is required for the toxicity we observe. (3) Compare the type and degree of a biochemical modification of tau know as phosphorylation in human AD and mouse TBI brains and test our hypothesis that genetically altering tau phosphatase activity affects the response to and/or production of toxic forms of tau.