# Repetitive mTBI-induced neurobehavioral changes and CTE-like proteinopathy

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Repetitive mild closed head injury (rCHI) is a common form of mild traumatic brain injury (mTBI) among military
personnel in both combat and non-combat missions. rCHI can result in sustained cognitive decline and
neurobehavioral changes (such as anxiety and depression-like behaviors) [1]. More recently rCHI has also
been linked to the formation of a neurodegenerative condition called chronic traumatic encephalopathy (CTE).
CTE is pathologically characterized by protein aggregate deposit found in the cortex and other brain regions,
post-mortem. Two major proteins found in these CTE protein deposits are microtubule-associated protein Tau
and TAR DNA-binding protein (TDP-43) [2-5]. Patients with CTE may show symptoms of dementia, such
as memory loss, confusion, anxiety, depression and aggression, which generally appear years or decade(s)
after the occurrence of neurotrauma. The Central Hypothesis to be tested is that chronic cognitive and
neurobehavioral changes following repetitive mTBI (rCHI) is closely linked to post-injury Tau and TDP-43
proteinopathy development. In addition, the proposed work will not only allow us to test this hypothesis, but
also enable us to validate novel CTE biomarkers tests as well as to examine a novel Tau, TDP-43
proteinopathy-based immunotherapy strategy towards improvement of chronic neurobehavioral deficits. Three
specific aims are proposed in this application to address the central hypothesis. In Specific Aim 1, we will
subject wildtype mice to repetitive close head injury (rCHI) and follow them from subacute to chronic period (up
to 18 mo.) to characterize cognitive and neurobehavioral changes, overall neuropathology and their correlation
with time-dependent CTE-like Tau/P-tau and TDP-43 protein accumulation /proteinopathy signatures in brain
tissue and biofluid. In Specific Aim 2 we will subject human-tau (hTau) transgenic mice and TDP-43
overexpressing transgenic mice to rCHI and follow them from subacute to chronic period to examine if they
develop worsened cognitive and neurobehavioral changes, neuropathology and accelerated, exaggerated
Tau/TDP-43 proteinopathy signatures in brain tissue and biofluid. Lastly, in Specific Aim 3, we will combine our
learning from rCHI models in Aim 1 & 2 to test potential effects of Tau/P-Tau and TDP-43 immunization as
novel immunotherapy for reducing rCHI-induced Tau and TDP-43 proteinopathy load and mitigating chronic
cognitive, neurobehavioral and neuropathological changes in wildtype, hTau, TDP-43 transgenic and/or
hTau/TDP-43 double transgenic mouse lines. This proposed systemic study will advance our understanding of
the neurobehavioral (anxiety, depression, cognitive dysfunctions) and their potential linkage to the
biochemical/protein changes of aggregation-prone proteins such as Tau and TDP-43 (proteinopathy) and CTE-
like neurodegenerative cascade during the chronic phase of TBI. Such knowledge can translate into the ability
for VA to devise better management tools and...

## Key facts

- **NIH application ID:** 10230980
- **Project number:** 5I01RX001859-05
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** KEVIN Ka Wang WANG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-11-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230980

## Citation

> US National Institutes of Health, RePORTER application 10230980, Repetitive mTBI-induced neurobehavioral changes and CTE-like proteinopathy (5I01RX001859-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10230980. Licensed CC0.

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