# Alcohol and traumatic brain injury; neuronal and behavioral consequences

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2020 · $228,688

## Abstract

ABSTRACT
Alzheimer's disease and Alzheimer's disease-related dementias are a growing challenge in the current aging
population, with no known treatments capable of stopping or reversing the progression of neurodegeneration.
Traumatic brain injury (TBI) results in enhanced neuronal loss, a hallmark of Alzheimer's disease (AD), and
increases the risk of neurodegenerative disorders. The biochemical mechanism(s) underlying neuronal loss post
TBI (in humans and rodents) remain to be determined. One possible mechanism underlying post-TBI
neurodegeneration is altered neuronal protein degradation and mitochondrial function. Protein and mitochondrial
turnover defects lead to accumulation of pathological proteins (e.g., tau, TDP-43, and amyloid-β [Aβ]), and are
considered major contributing factors in the pathogenesis of neurodegenerative diseases, like AD. The ubiquitin
pathway is essential for regulating neuronal protein and mitochondrial turnover, and defects in this pathway lead
to abnormal protein deposition post TBI. Studies from the lab of our collaborator, Dr. Desai, have identified
conjugation of ubiquitin-like protein ISG15 (interferon-stimulate gene 15) to cellular proteins, termed ISGylation,
as a mechanism underlying neurodegeneration. Free ISG15 and ISGylation are elevated in fibroblasts and brains
obtained postmortem from subjects diagnosed with ataxia telangiectasia, lymphocytes obtained from subjects
diagnosed with AD, and spinal cords of veterans who suffered TBI and were later diagnosed with amyotrophic
lateral sclerosis (ALS). ISG15 expression is regulated by type I interferons (IFNβ), forming an IFNβ/ISGylation
axis. Our preliminary data collected from alcohol-naïve TBI rats (as described in the parent grant) show increased
ISGylation in the dorsal hippocampus; an important brain region involved in memory and learning processes,
relative to sham controls. Whether post-TBI upregulation of ISGylation inhibits neuronal protein and
mitochondrial turnover remains to be investigated. Moreover, it is not known whether alcohol consumption post
TBI exacerbates upregulation of the IFNβ/ISGylation axis. However, neuroinflammation commonly precedes and
is associated with neurodegeneration and our data show accentuated neuroinflammation at the site of injury in
alcohol-exposed TBI animals. These findings support the prediction that alcohol-induced increases in
neuroinflammation will enhance post-TBI neurodegeneration. We hypothesize that post-TBI activation of the
IFNβ/ISGylation axis inhibits ubiquitin-dependent neuronal protein and mitochondrial turnover resulting in
accumulation of toxic proteins (i.e., tau, Aβ), defective mitochondria, and neurodegeneration, and that these
effects will be exacerbated by alcohol consumption. Two specific aims will use the same TBI experimental model
as the parent grant to measure neuropathological changes that increase risk for Alzheimer's disease in adult
female and male rats. Results generated from these studi...

## Key facts

- **NIH application ID:** 10123734
- **Project number:** 3R01AA025792-03S1
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Nicholas Warren Gilpin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $228,688
- **Award type:** 3
- **Project period:** 2018-05-10 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123734

## Citation

> US National Institutes of Health, RePORTER application 10123734, Alcohol and traumatic brain injury; neuronal and behavioral consequences (3R01AA025792-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10123734. Licensed CC0.

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