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CTE and Neurodegeneration

Garrett Heinrich
Tags: Neuroscience

As summer ends and the fall season rolls in, football fans begin to pack stadiums to watch their favorite teams play their most hated rivals. Often, the most exciting plays involve big hits that stop players in their tracks and bring the fans to their feet. Unfortunately, these big hits are not good for the players’ health, which becomes visible when they have trouble leaving the field or even maintaining consciousness. These big hits can shake the brain even when wearing a helmet, and cause a concussion that can produce headaches, blurry vision, and other problems. As athletes have become bigger, stronger, and faster and able to produce more force than ever before, concussions are commonplace, even with advancements in helmet technology. The negative long-term effects of repeated concussions have been studied in boxers and soldiers for decades. But a new threat becoming better understood…that of repeated subconcussive events that occur in routine blocking and tackling. They do not get the cheers from the fans but may have just as devastating effects later on in these athletes’ lives.

What is CTE?

A progressive neurodegenerative disease known as chronic traumatic encephalopathy (CTE) has been identified in some athletes of contact sports (e.g., boxing or football) and individuals with repetitive brain trauma (RBT) or traumatic brain injuries (TBI), such as veterans with combat experience, people with epilepsy, or subjects of physical abuse. Repetitive injury begins to impair the brain’s restorative ability and leads to atrophy of the brain tissue. Ultimately, cognitive and motor dysfunction is similar to people with Parkinson’s or Alzheimer’s disease. Unfortunately, there are few methods to detect CTE in people besides examining their brain posthumously, and the early stages of the disease are still not well understood.

The risk of CTE is not limited to men. Studies on female athletes show an even greater susceptibility to concussions and brain injury than in men, though the data is more limited in women. The reasons for this are unclear, though differences in neck strength, athletic technique, inflammatory response to injury, and hormonal differences which could render females less protected have been proposed. The effects of progesterone are unclear, as it has been shown to be neuroprotective, but progesterone levels are also associated with concussion, and decrease with brain injury. Clearly, more work is needed, and the Enzo species-independent Progesterone ELISA kit can be a valuable tool towards this goal.

How does CTE begin? One hypothesis for the early development of CTE is that soon after the injury-causing impact, the neurotransmitter glutamate is released, subsequently acting on its receptors and initiating a cascade that results in an excess of calcium released into the cell cytoplasm, causing what is known as excitotoxicity. Calcium-induced excitotoxicity induces mitochondrial dysfunction and oxidative stress, producing reactive oxygen species (ROS) and nitric oxide (NO). Repeated injury extends this excitotoxicity and begins to impair the brain’s restorative ability, leading to atrophy of the brain tissue. When the brain cannot restore itself, the protein tau cannot stabilize microtubules that help make up the brain structure and lead to phosphorylated tau accumulation and neurofibrillary tangles (NFTs) that impair signaling. Enzo offers several solutions to investigate these processes. The SCREEN-WELL Ionotropic and Metabotropic Glutamatergic ligand libraries can be used to screen modulators of this glutamate signaling. Calcium mobilization can be studied in vitro with the FLUOFORTE Calcium assay kit and the GFP-CERTIFIED FLUOFORTE Calcium assay kit. The FLUOFORTE dye binds to intracellular calcium and can be detected by fluorescence (Figure 1). ROS and NO can be monitored in live cells with the ROS-ID Total ROS detection kit and ROS-ID NO Detection kit, respectively. Phosphorylated tau at the Serine-262 residue in the microtubule-binding domain can be detected by western blot using the [pSer262]Tau polyclonal antibody.

Figure 1. Binding of intracellular calcium by the FLUOFORTE dye

Are tests available to determine if CTE is occurring?

Identifying early stages of CTE or markers of early pathogenesis non-invasively is critical to screen patients at risk and prevent further damage. Still, so far, good markers are lacking. Blood measurements of phosphorylated tau at the threonine 181 site have been associated with CTE. They may be an effective screen to determine if patients should undergo more invasive testing by positron emission tomography (PET) scanning or measuring markers in the cerebral spinal fluid (CSF). The Tau (phospho Thr181) polyclonal antibody can be used to detect this marker in Western blot or immunohistochemical applications. Some of the same neuroinflammatory chemicals elevated after brain trauma may also be early signals for CTE. These cytokines include interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF), and can each be measured in the plasma or serum by ELISA.

The transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as having many functions in the brain through its RNA-binding properties and is believed to play a role in brain health. Loss of TDP-43 function results in impaired splicing of pre-mRNA. Mutations in TARDBP, the gene encoding TDP-43, have been found in the brain of patients with amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Gain of TDP-43 results in the formation of ubiquitinylated aggregates and neural degradation. The build-up of TDP-43 found in these neuropathies may be caused in part by impaired autophagy and the resulting reduced TDP-43 clearance. The Axxora catalog has several antibodies to TDP43 that can be used in Western blot analysis (PSC-4285 and PSC-4283) and our CYTO-ID Autophagy detection kit 2.0 can fluorescently label autophagic vacuoles in live cells.

CTE has similarities and differences with other neurodegenerative diseases, such as Alzheimer’s disease (AD). While both result in cognitive impairment and changes in mood, behavior, and motor control, the presence of beta-amyloid plaques is less common and more diffuse in many cases of CTE compared to AD. One way to detect beta-amyloid in tissue sections is with our PROTEOSTAT dye or Congo Red. In addition, TDP-43 positive inclusions are much more prevalent in CTE compared to AD.

So avoid CTE by not getting hit in the head a lot, right?

The short answer is yes, but what to avoid becomes a bit more complicated. As we learn more about CTE, it is becoming clear that the risk is not limited to violently physical injury or to those who experience “knockout” hits in sport. Traumatic impacts result in concussive symptoms, including headaches, dizziness, balance disturbances, drowsiness, and memory or concentration impairments. A subconcussive event is less severe and does not result in concussive symptoms. But ongoing studies are evaluating whether chronic subconcussive events are enough to cause CTE over time. So whether even athletes playing sports such as soccer, where hitting the ball with your head is typical or youth football, where the impacts are not as extreme as in college or professional leagues, may show effects of CTE later in life is yet to be confirmed. Researchers are also investigating whether single traumatic events are enough to start the cascade of neurodegeneration.

There is no standard therapy for CTE, and current treatments only help patients manage the symptoms they are experiencing. As the molecular mechanisms behind CTE become clearer, new treatments may become available. But for now, prevention through protective equipment, rule changes to protect participants, and incorporating safe techniques in play are the best options to avoid complications of CTE later in life.

How can Enzo help guide your neurology research?

Do you have more questions on chronic traumatic encephalopathy and how to find the best assays and molecules for your research? Reach out to our Technical Support Team. We will be happy to assist!

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