MECHANISMS UNDERLYING AMYLOID-BETA AND TAU PATHOLOGIES FOLLOWING TBI

Washington University, Saint Louis MO

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Abstract

PROJECT SUMMARY Traumatic brain injury (TBI) is a major cause of death and disability, especially among young people. Pathological processes involving the amyloid-beta (A¿) peptide and tau protein are accelerated by acute TBI. Moderate to severe TBI substantially increases the risk of dementia of the Alzheimer type later in life. A¿ deposition is a major pathological hallmark of Alzheimer disease (AD) and pathological tau abnormalities are seen in AD and many other neurodegenerative conditions. These A¿ and tau abnormalities may also contribute to short-term adverse outcomes, as some forms of these proteins can have immediately neurotoxic effects. Additional studies have found that A¿ can cause or accelerate tau pathology under some conditions, thus A¿ may play a central role in both pathologies. However, the mechanisms underlying A¿ and tau abnormalities following TBI are incompletely understood, in large part due to the lack of an appropriate small animal model. Preliminary results indicate that experimental controlled cortical impact TBI in 3xTg-AD mice results in intra-axonal A¿ deposition in the injured fimbria and accelerated tau pathology in the contralateral hippocampus within 24 hours of injury. 3xTg-AD mice produce both human A¿ and human tau with mutations that accelerate pathology, but in our experiments they were injured at young ages before significant neuropathological abnormalities are normally present. The long-term objective of the proposed project is to test the central hypothesis that A¿ is a key mediator of adverse behavioral and neuropathological outcomes following TBI. The specific aims are 1) to determine the mechanisms responsible for accelerated A¿ deposition following TBI in the 3xTg-AD mouse model, 2) to determine if TBI-induced A¿ overproduction plays a causal role in tau hyperphosphorylation and accumulation, and 3) to determine the effects of TBI-induced acute A¿ accumulation on sub-acute outcomes including behavioral performance axonal injury, neuronal cell loss, and tau pathology. Methods used will include a) colocalization studies of amyloid precursor protein (APP) and A¿ with several proteolytic enzymes thay may cleave APP to produce A¿. b) pharmacological or genetic inhibition of several potential A¿ producing enzymes, c) analysis of tau pathology in several lines of transgenic mice with and without human A¿, d) assessment of behavioral performance in mice treated with A¿-targeted therapeutics or with genetic manpulations that eliminate A¿ production. If successful, these experiments will result in an improved understanding of the mechanisms underlying A¿ and tau abnormalities following TBI. This may facilitate development of therapeutic strategies targeting A¿ and tau, which could ultimately improve outcomes and reduce the subsequent risk of dementia and adverse cognitive outcomes in TBI patients.