The Role of Acetylated Tau in the Increased Risk of Alzheimer s Disease After Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) is currently the signature injury of our military, with 16,000 Veterans diagnosed with TBI last year. In addition, over 430,000 Veterans suffered a TBI between 2000 and 2020, according to the Defense and Veterans Brain Injury Center. Analysis of over 350,000 Veterans has revealed that TBI, even without loss of consciousness, more than doubles the risk of age-related dementia, including Alzheimer’s disease (AD). Moreover, the risk is nearly four times higher after moderate-to-severe TBI. In 2015, an estimated 486,000 Veterans were living with AD, and since 2008 the annual number of Veterans newly diagnosed with dementia has increased more than 22%. Although TBI is the greatest environmental cause of AD, the underlying mechanism by which TBI accelerates the onset of AD is still not known. Given the high rate of TBI in the military, this is a critical issue for both Veterans and active military personnel. In order to develop medicines that will protect patients from developing AD after TBI, we must first understand the mechanism by which this occurs. We recently identified that nitrosative stress in the form of overproduction of nitric oxide (NO) after TBI drives a signaling cascade initiated by S-nitrosylation, which is attachment of a nitric oxide group (-NO) to the glyceraldehyde phosphate dehydrogenase (GAPDH) proteins. Modified GAPDH then implements downstream signaling events that culminate in early accumulation of toxic acetylated-tau (ac-tau) protein in neurons, leading to axonal degeneration and cognitive impairment. Amyloid beta peptide, such as accumulates in AD, causes this same S-nitrosylation of GAPDH, and we have shown that TBI causes tau acetylation at the same sites in both people and mice as has been previously identified in the brains of patients with AD. We have also shown that blocking GAPDH S-nitrosylation with omigapil, or blocking downstream activation of p300/CBP acetyltransferase (which adds acetyl group to tau protein) with diflunisal, both potently block TBI-induced accumulation of ac-tau and its neurodegenerative and cognitive consequences. We further determined that patient usage of diflunisal is epidemiologically associated with decreased incidence of AD and clinically significant TBI. Lastly, we have reported that accumulation of ac-tau in human AD brain is significantly increased by a prior history of TBI. Importantly, we have already shown that TBI accelerates the onset of AD-like disease in 5xFAD, animal model of AD. Based on our findings, we hypothesize that early accumulation of neuronal ac-tau is a mechanistic link between TBI and advanced onset of AD. Specifically, we hypothesize that early ac-tau accumulation in neurons after TBI accelerates the development of AD, and that pharmacologically blocking ac-tau accumulation by omigapil or diflunisal will prevent TBI-induced advancement of AD. We also hypothesize that genetically mimicking ac-tau will advance the onset of AD. We anticipate that the results derived from this effort will lead to novel and efficacious therapeutic interventions that provide unique benefits to military personnel, Veterans, and civilians by protecting the brain from AD after TBI.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210129
Entities
People
- Edwin Vazquez-rosa
Organizations
- Case Western Reserve University
- United States Army