Traumatic brain injury (TBI) has been a major cause of death and threat to optimal brain function throughout the entire history of human existence. Delayed secondary injury processes that could be reversed or prevented are important therapeutic targets for TBI. The focus of this project is on secondary injury processes involving the protein tau. Abnormal aggregations of tau have been detected hours to days after injury in the brains of many TBI patients. Tau may be involved in the early development of dementia similar to Alzheimer's disease, and tau is the hallmark of chronic traumatic encephalopathy seen in boxers, football players, and military personnel with TBIs. Importantly, an up-to-date definitio of the spectrum of tau pathology now includes not only tau that is visible under the microscope, but also small clusters of tau called oligomers and aggregated forms of tau that can spread through the brain by triggering additional tau aggregation. However, the mechanisms underlying tau pathologies following TBI are not understood, in large part due to the lack until recently of a appropriate small animal model. To address this, we developed the first transgenic mouse model which recapitulates many aspects of tau pathology following experimental TBI. 1) For our first aim, we now propose to test the hypothesis that tau oligomers and spreading tau aggregation contribute to delayed brain degeneration following TBI. These studies will be performed in collaboration with Dr. Rakez Kayed at the University of Texas, Galveston and Dr. Marc Diamond at Washington University, two researchers working at the cutting edge of tau biology. 2) Intriguingly, treatment with an inhibitor of an enzyme called c-jun N-terminal kinase (JNK) before injury reduced TBI-related tau pathology in the brain. For our second aim, we propose to test whether treatment with a JNK inhibitor at therapeutically realistic times after injury blocks tau pathology and improves outcomes in mice. We will assess both short term and longer-term pathological and behavioral outcomes, including innovative tests of social behavior and mood regulation in mice. 3) There are three types of JNK in the brain called JNK1, JNK2 and JNK3. Mice without JNK1 or JNK2 have problems with immune system function whereas mice without JNK3 are actually protected from other types of brain insults. Our hypothesis is that JNK3 is playing a key role and that JNK3 would make a better and safer target for new therapeutics than nonselective JNK inhibitors. We propose for our third aim to create antisense oligonucleotides specifically targeting each type of JNK. We will treat mice with these antisense oligonucleotides and determine whether this reduces tau pathology and improves outcomes following TBI. These antisense oligonucleotides have the potential to be used in human TBI patients, as there are two antisense therapeutics already approved and approximately 35 more in various stages of human clinical trials. Our collaborators, Dr. T.M. Miller at Washington University and Dr. Eric Swayze of Isis Pharmaceuticals are among the world's experts in antisense treatments. The broad, long term goals are to uncover the mechanisms leading to secondary injury processes involving tau and develop therapeutics to block them, with the hope that this would improve outcomes following TBI. The worldwide interest in athletes and military personnel with tau pathology and chronic traumatic encephalopathy underscores the urgency of this line of investigation.

Public Health Relevance

of this project is that if successful, it will result in a deeper understanding of the mechanisms underlying important aspects of the pathology of traumatic brain injury. A deep understanding of these mechanisms may allow development of new treatments to prevent long-term problems such as chronic traumatic encephalopathy and dementia following traumatic brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065069-07
Application #
8870447
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
2009-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wildburger, Norelle C; Esparza, Thomas J; LeDuc, Richard D et al. (2017) Diversity of Amyloid-beta Proteoforms in the Alzheimer's Disease Brain. Sci Rep 7:9520
Lebois, Evan P; Schroeder, Jason P; Esparza, Thomas J et al. (2017) Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model. ACS Chem Neurosci 8:1177-1187
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 7:483-495
Esparza, Thomas J; Wildburger, Norelle C; Jiang, Hao et al. (2016) Soluble Amyloid-beta Aggregates from Human Alzheimer's Disease Brains. Sci Rep 6:38187
Kummer, Terrance T; Magnoni, Sandra; MacDonald, Christine L et al. (2015) Experimental subarachnoid haemorrhage results in multifocal axonal injury. Brain 138:2608-18
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 (2015) Array tomography for the detection of non-dilated, injured axons in traumatic brain injury. J Neurosci Methods 245:25-36
Brody, David L; Benetatos, Joseph; Bennett, Rachel E et al. (2015) The pathophysiology of repetitive concussive traumatic brain injury in experimental models; new developments and open questions. Mol Cell Neurosci 66:91-8
Friess, Stuart H; Lapidus, Jodi B; Brody, David L (2015) Decompressive craniectomy reduces white matter injury after controlled cortical impact in mice. J Neurotrauma 32:791-800
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

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