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.

Public Health Relevance

Traumatic brain injury- such as from motor vehicle accidents, falls, assault, or military operations- is a common cause of impaired thinking and memory immediately after the injury and increases the chances of developing Alzheimer's disease later in life. The goal of this project is to use genetically engineered mice to improve our understanding of the causes of these thinking and memory problems and increased risk of Alzheimer's disease. If successful, the results of the project may point to ways to develop effective treatments to prevent or reverse these problems in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065069-04
Application #
8269685
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2009-07-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$325,850
Indirect Cost
$111,475
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Li, Zhongqi; Oganesyan, Diana; Mooney, Rachael et al. (2016) L-MYC Expression Maintains Self-Renewal and Prolongs Multipotency of Primary Human Neural Stem Cells. Stem Cell Reports 7:483-95
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Bennett, Rachel E; Brody, David L (2015) Array tomography for the detection of non-dilated, injured axons in traumatic brain injury. J Neurosci Methods 245:25-36
Magnoni, Sandra; Mac Donald, Christine L; Esparza, Thomas J et al. (2015) Quantitative assessments of traumatic axonal injury in human brain: concordance of microdialysis and advanced MRI. Brain 138:2263-77
Bennett, Rachel E; Brody, David L (2014) Acute reduction of microglia does not alter axonal injury in a mouse model of repetitive concussive traumatic brain injury. J Neurotrauma 31:1647-63
Bennett, Rachel E; Esparza, Thomas J; Lewis, Hal A et al. (2013) Human apolipoprotein E4 worsens acute axonal pathology but not amyloid-β immunoreactivity after traumatic brain injury in 3xTG-AD mice. J Neuropathol Exp Neurol 72:396-403
Esparza, Thomas J; Zhao, Hanzhi; Cirrito, John R et al. (2013) Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73:104-19

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