Widespread tau-containing neurofibrillary tangles and A? plaque pathologies are present in the brains of patients with repetitive mild human traumatic brain injuries (TBI) and of patients many years after a single severe TBI. The overall goal of the proposed project is to build a novel in vitro TBI model in order to clarify the intracellular pathways that link mechanical neuronal injuries to tau abnormalities. To achieve this goal, we will test the central hypothesis that neuronal injuries caused by mechanical forces lead to tau hyperphosphorylation, which induces subsequent tau mislocalization and tau-mediated synaptic deficits. We will pursue two Specific aims:
In Aim 1, we determine the cellular mechanism underlying mechanical injury- induced tau-mediated morphological deficits in dendritic spines. Neurons will be stretched using three TBI protocols to mimic one single severe TBI, repeated mild injuries and bomb blast waves. We will determine whether the tau mislocalization caused by the stretching protocols depends upon tau hyperphosphorylation, activation of tau kinases (CDK5 and GSK3) and the production of A? oligomers. We will also test the roles of tau and Fyn in spine loss caused by neuronal injuries.
In Aim 2, we will clarify the cellular mechanism underlying mechanical injury-induced tau-mediated functional deficits in dendritic spines. We will characterize pre- and/or post-synaptic deficits caused by mechanical injuries in our in vitro model and will determine whether these deficits are mediated by endogenous tau, tau hyperphosphorylation, the production of A? oligomers and the activation of calcineurin. This will be the first in vitro TBI model that can replicate DAI and tau abnormalities. Using this novel model, we will clarify the tau-mediated link between TBI, AD, and FTD at a cellular level, opening a new area to the field of TBI research.

Public Health Relevance

The project is based upon our very novel finding that mechanical stretching induces diffuse axonal injuries and tau mislocalization to dendritic spines, which are two key features of traumatic brain injuries (TBI). The overall goal of the proposed project is to build a novel in vitro TBI model in order to clarify the intracellular pathways that ink mechanical neuronal injuries to tau abnormalities and subsequent synaptic deficits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS096437-02
Application #
9210663
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Bellgowan, Patrick S F
Project Start
2016-02-01
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$165,273
Indirect Cost
$52,773
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455