Researchers at the Harrington Discovery Institute in Cleveland have shown that traumatic brain injury (TBI) induces acetylation of the tau protein at sites that are also acetylated in human Alzheimer’s disease (AD)—revealing a potential mechanistic link between TBI and AD. The team also suggested that levels of acetylated tau (ac-tau) could be a potential biomarker indicating a TBI.
In addition, the investigators found that two non-steroidal anti-inflammatory drugs (NSAIDs), salsalate and diflunisal, were potently neuroprotective after TBI in mice, while an analysis of human records indicated that use of either drug for other indications was associated with much lower incidences of clinically diagnosed TBI, and of AD.
“This work has a number of potential clinical implications,” explained Edwin Vázquez-Rosa, Ph.D., co-first author on the study, which is reported in Cell. “First, it shows that the medicines salsalate and diflunisal provide previously unidentified neuroprotective activity by this new mechanism, and that in the course of being prescribed these medicine for traditional indications patients appear to also be relatively protected from developing neurodegenerative conditions. Accordingly, these medicines may also help protect TBI patients from developing AD. Finally, our work provides a new blood biomarker of neurodegeneration in the brain after TBI that could be harnessed to stage severity and progression of nerve cell deterioration after injury.”
Violent blows or jolts to the head can cause traumatic brain injury, and there are currently about five million people in the U.S. living with some form of chronic impairment after suffering a TBI, the authors noted. Even in a mild form, TBI can lead to lifelong nerve cell deterioration associated with a wide array of neuropsychiatric conditions. Tragically, there are no medicines to protect nerve cells after injury, they wrote. “At present, treatments for TBI focus on patient stabilization and mitigation of symptoms, and there are no medicines that specifically target the pathophysiological processes that drive neurodegeneration after brain injury.” Behind aging and genetics, TBI is also the third leading cause of Alzheimer’s disease (AD), yet the link between these two conditions is not understood.
A number of studies have previously reported increased acetylation of tau protein in the brain cells of AD patients. But scientists don’t really understand how this modification comes about, or its role in the disease process. “ … these studies did not establish the driving forces or pathologic significance of the findings,” the team continued.
“Normally, tau functions in nerve cells to maintain the appropriate structure of the axon, which is the nerve cell extension required for nerve cells to communicate with one another,” said Harrington Discovery Institute (HDI) Investigator Andrew A. Pieper, M.D., Ph.D., who is senior author of the newly reported study. “Given the relationship between AD and TBI, we wondered whether elevated acetylated-tau (ac-tau) might also occur in TBI, and if so, then whether this could provide an experimental platform to study its potential role in nerve cell deterioration.” Pieper is Director of the HDI Neurotherapeutics Center at University Hospitals (UH), Morley-Mather Chair in Neuropsychiatry at UH, Director of the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center, and VA Geriatric Research, Educational and Clinical Care (GRECC) Investigator.
The team’s studies first demonstrated that ac-tau increased rapidly in multiple forms of TBI in mice and rats, and persisted chronically when nerve cell degeneration was untreated. They also showed that increased ac-tau in the human AD brain was further exacerbated when the AD patient also had a prior history of TBI.
“Our research showed that after ac-tau rises, a specific structure at the junction of the nerve cell body and its axon, called the axon initial segment, breaks down,” explained Min-Kyoo Shin, Ph.D., co-first author of the study. “As a result, tau is no longer appropriately sequestered in axons. This leads to axonal degeneration, followed by neurologic impairment.”
The team tested therapeutic interventions after TBI at each of the three nodal points in the new signaling pathway that they identified as leading to increased nerve cell ac-tau after injury. Using known medicines or experimental drugs, they saw that all three points provided effective therapeutic opportunity. Through their experiments they also discovered that the NSAID drugs salsalate and diflunisal, were particularly neuroprotective after TBI in mice. Relative to all other NSAIDs and distinct from their anti-inflammatory property, these two drugs inhibited the acetyltransferase enzyme in nerve cells that adds the acetyl group onto tau protein after brain injury.
Next, they examined more than seven million patient records and learned that usage of either salsalate or diflunisal was associated with decreased incidence of both AD and clinically diagnosed TBI, compared to usage of aspirin in other patients for the same time period. The protective effect was stronger for diflunisal than for salsalate, which correlates with diflunisal’s superior potency, relative to salsalate, in inhibiting the acetyltransferase enzyme. The NSAID aspirin was used as a comparison group because it does not inhibit the acetyltransferase. “In aggregate, the animal and human data presented here offer compelling support for a neuroprotective effect of reducing ac-tau, which supports further exploration of the potential protective efficacy of diflunisal or salsalate in patients with TBI or AD,” the authors concluded.
Because the tau protein freely diffuses from the brain into the blood, the researchers also examined whether ac-tau might also be elevated in the blood after TBI. In mice, they found that blood levels of ac-tau correspond tightly with brain levels, and that blood levels returned to normal when mice are treated with therapeutics that lowered brain ac-tau and thereby protected nerve cells.
Importantly, the team also found that ac-tau was significantly increased in the blood of human TBI patients. “Here, we have shown that ac-tau levels rapidly rise in the blood of both rodents and humans after brain injury, and that serum levels decline proportionally with protective treatments that target the underlying signaling cascade,” the investigators wrote. “… our results establish that reducing tau acetylation through multiple different points of therapeutic intervention after brain injury offers a previously unanticipated neuroprotective strategy, and quantifying tau acetylation in the blood provides an additional peripheral biomarker of brain injury.”
Robert A. Bonomo, M.D., associate chief of staff at VA Northeast Ohio Healthcare System and professor at Case Western Reserve School of Medicine added, “Many of our patients suffer from TBI or AD. These important findings will have a tremendous, long-term impact on our Veteran population.”
Next steps in the research may involve further investigation of the applicability of ac-tau as a biomarker in neurodegenerative disease and the potential utility of diflunisal or salsalate as neuroprotective medicines for people, as well as deeper study of the mechanisms by which ac-tau causes nerve cell deterioration. And as the authors noted, “Future studies will focus on the interplay between tau acetylation and the myriad other pathological post-translational modifications of tau that have been reported, including phosphorylation and ubiquitination.”