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Tau Isoforms in Chronic Traumatic Encephalopathy: Paving the Way for Diagnostics, Targeted Therapy

The link between contact sports and chronic traumatic encephalopathy has gained increased scrutiny in recent years, largely due to research into the subject by Dr. Ann McKee of Boston University. In this post, we discuss a recent publication from Dr. McKee’s team which used multiplex immunohistochemistry in combination with other approaches to gain a better understanding of the cellular and molecular changes in CTE brains.

In recent years, there’s been increasing interest in the risks of brain injury posed by contact sports, especially football. Individuals like college and professional football players, who are more likely to suffer repeated head injuries, are also at increased risk for developing chronic traumatic encephalopathy (CTE). This neurodegenerative disorder is slow acting, and difficult to detect.

The symptoms of CTE can include memory loss, confusion, depression, anxiety, and progressive dementia — symptoms that overlap with many other neurological conditions. These signs typically appear years, even decades, after the last brain trauma. There is no definitive way to diagnose the disease in living patients with traditional brain imaging methods such as MRI or CT, nor is there any known treatment.

A great deal of the knowledge we do have on this disease can be credited to Ann McKee, MD, Professor of Neurology and Pathology at Boston University and Director of the BU Chronic Traumatic Encephalopathy Center. In 2017, Dr. McKee led a widely publicized study which examined the brains of 202 football players posthumously. They found evidence of CTE in 110 of the athletes.

Image of a normal brain and a brain with advanced chronic traumatic encephalopathy.

Source: Boston University Center for the Study of Traumatic Encephalopathy (CC-BY-NC-ND 4.0).

Dr. McKee noted the selection bias: many families donated the brains of former players because they had shown symptoms of CTE. Still, the number was disproportionately higher than would be expected from CTE occurrences in the general population. The study led to increased attention on safety regulations in the NFL. In 2018, Dr. McKee was recognized as one of TIME’s 100 Most Influential People.

A lack of biomarkers

CTE is a tauopathy and results in abnormal tau isoform accumulation in the brain. More specifically, it’s characterized by deposits of hyperphosphorylated tau (p-tau) protein starting at the sulcal depths and progressing to diffuse neocortical, allocortical and brainstem structures. To develop in vivo diagnostic biomarkers for the detection of CTE, we must form a better understanding of the cellular and molecular changes that occur in the brain during CTE progression.

Dr. McKee’s team at the BU Chronic Traumatic Encephalopathy Center sought to do just that in a recent study. Using multiple biological and histological approaches, including multiplex immunohistochemistry, they characterized tau isoform signatures in post-mortem human brain tissue across a wide range of CTE stages. Their results were published in Brain Pathology.

The BU team observed multiple correlates with CTE severity. They first quantified the total levels of normal and abnormal forms of tau with immunoblot studies, finding that oligomeric tau increases with CTE severity, while monomeric tau decreases. 3R and 4R forms of oligomeric tau (with three and four microtubule binding domain repeats, respectively) were also shown to increase with CTE severity.

Using multiplex fluorescent immunohistochemistry (IHC), they observed 3R and 4R p-tau accumulation in perivascular lesions and analyzed the ratio of 4R to 3R. While 4R was predominantly expressed in early stages of CTE, the ratio shifted towards 3R in later stages.

These findings suggest that 4R tau abnormalities in perivascular neurons are some of the earliest indicators of CTE in the post-mortem brain. Further research is needed to understand the mechanisms behind these observations and determine how predominantly 3R cases differ pathologically from those predominantly 4R.

The role of multiplex IHC

In this study, 4R Tau, 3R Tau, AT8, MAP2, GFAP, and Iba1 were visualized through multiplex IHC on post-mortem brain tissue. The researchers performed immunofluorescence staining using the Opal Polaris 7-Color Manual IHC Detection Kit to and imaged tissue sections on the Vectra Polaris system.

As noted earlier, the team used multiplex IHC to determine the ratios of 4R to 3R tau isoforms and understand how that ratio shifts across different CTE stages. It was also used to verify morphological assessments of cells to determine whether 3R or 4R was present in neurons or astrocytes. This study highlights the ability of multiplex IHC to enable high-quality, in situ analysis of brain tissue for biomarker quantification and phenotyping.

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