HomeENGLISH MAGAZINEBrain injury and dementia: is tau protein the "traumatic" connection between them?

Brain injury and dementia: is tau protein the “traumatic” connection between them?

Violent blows or jolts to the head can cause traumatic brain injury (TBI), and there are currently about five million people in the U.S. living with some form of chronic impairment after suffering a TBI. 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. Behind aging and genetics, TBI is the third leading cause of Alzheimer’s disease, yet the link between these two conditions is not understood. In a new study, published online in prestigious scientific journal Cell, researchers have discovered a new way to prevent brain nerve cells from deteriorating after injury, which also revealed a potential mechanistic link between TBI and Alzheimer disease (AD). Their discovery also yielded a new blood biomarker of nerve cell degeneration after injury, which is significant because there is an urgent need for mechanism-based blood biomarkers that can diagnose TBI and stage its severity.

Prior to this study, it had been previously reported that a small protein in nerve cells, called tau, was modified by a chemical process called acetylation in the post-mortem brains of AD patients. But how this modification came about, as well as its role in the disease process, was not understood. 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. It is the same protein implicated in the group of neurodegenerative disorders called tauopathies, where the protein (among others) is mutated or alterated. In Alzheimer disease, instead, tau protein is only aggregated in structures called neurofibrillary tangles (NFTs). These were originally tought to be causal for the condition, while later they have been recognized just as an hallmark of cellular damage, being composed of phosphorylated and acetylated forms or proteins.

Andrew A. Pieper, MD, PhD, neuropsychiatrist and Director of the HDI Neurotherapeutics Center at University Hospitals and Director of the Translational Therapeutics Core of the Cleveland Alzheimer’s Disease Research Center, is the senior author on the study. Given the relationship between AD and TBI, his team 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. Scientists discovered 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 the increased Ac-tau in human AD brain was further exacerbated when the AD patient also had a prior history of TBI. After Ac-tau rises, the axon initial segment breaks down. As a result, tau is no longer appropriately sequestered in axons, which leads to axonal degeneration.

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. Strikingly, they found that two NSAIDs (anti-inflammatory drugs), salsalate and diflunisal, were potently neuroprotective after TBI in mice. Relative to all other NSAIDs and distinct from their anti-inflammatory property, these two medicines inhibit the acetyltransferase enzyme in nerve cells that adds the acetyl group onto tau protein after brain injury. Beside nuclear acetyltransferase, some members of this family is also represented in cytoplasm and drives protein acetylation under specific biological context. One of this is the enzyme KAT5, whose action is antagonized by the deacetilase HDAC-6 acting on cytoskeleton.

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 in diflunisal and salsalate, which correlates with diflunisal’s superior potency in inhibiting the acetyltransferase enzyme, relative to salsalate. Aspirin was used as a comparison group because it does not inhibit the acetyltransferase. Lastly, because the tau protein freely diffuses from the brain into the blood, the researchers 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 return to normal when mice are treated with therapeutics that lower brain ac-tau and thereby protect nerve cells. Importantly, they also found that Ac-tau was significantly increased in the blood of human TBI patients.

According to the team, this work has a number of potential clinical implications. First, it shows that the simple NSAIDS like 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, the research 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. Next steps in the research involve further investigation of the applicability of Ac-tau as a biomarker in neurodegenerative disease, as well as deeper study of the mechanisms by which Ac-tau causes nerve cell deterioration. But, most, important, the potential utility of diflunisal or salsalate as neuroprotective medicines for dedicated patients.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Zhou Y, Fang J et al. Alzheimers Res Ther. 2021; 13(1):24. 

Vázquez-Rosa E et al. PNAS USA 2020; 117(44):27667-675. 

Harper MM, Rudd D et al. Heliyon 2020 Feb 17; 6(2):e03374. 

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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