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 studies will form the basis of a grant application examining epigenetic mechanisms involved in activation of the IFNβ-/ISGylation axis as an underlying mechanism increasing the risk for Alzheimer's neuropathology post TBI.

PROJECT NARRATIVE Excessive alcohol drinking after traumatic brain injury (TBI) aggravates neurobehavioral outcomes and prevents or delays recovery from the injury. TBI results in enhanced neuronal loss and increases the risk of Alzheimer's disease (AD). These studies examine the underlying mechanisms of post-TBI neurodegeneration and AD risk.