In February of 2011, tragedy struck when Dave Duerson, a former Chicago Bears football player, committed suicide by shooting himself (1). However, Dave was not alone; his suicide joined the suicides and other violent endings to former and current football players such as Andre Waters (Philadelphia Eagles, Arizona Cardinals), Owen Thomas (U. Pennsylvania), and Kenny McKinley (Pittsburgh Steelers).
One could shrug off the deaths of these players are simple coincidence, if not for an elusive, yet chilling, central theme found in the depths of their brains: small, yet insidious, neurofibrillary tangles containing the microtubule-associated protein tau. Such tau-containing tangles are the molecular hallmarks of frontotemporal dementia (FTD) or Alzheimer’s Disease-riddled brains. The brains of people who are not diagnosed with FTD or Alzheimer’s Disease do not contain these tau tangles.
If that is the case, why in the world were Dave Dueson, Andre Waters, Owen Thomas and Kenny McKinley found to have these tau tangles? Furthermore, when Boston University examined the brains of 13 former and current football players who met violent ends (including suicide), all 13 players’ brains were found to have these same tau-containing tangles.
There is also the widespread assumption that FTD, and especially Alzheimer’s, are diseases of aging. Owen Thomas was only 21 when he committed suicide and was examined by autopsy; Kenny McKinley was 23. Furthermore, Dave Duerson may have suspected something was wrong with his brain when, shortly before his suicide, he left messages to his family saying, “Please, see that my brain is given to the NFL’s brain bank.”
Is there a new brain disease on the horizon that is causing football players to commit suicide? Amazingly, yes. Evidence is accumulating that football players, boxers, and other sports athletes have an increased chance of developing a condition called chronic traumatic encephalopathy (CTE), a neurodegenerative condition instigated not by old age or genetics, but by injury to the brain. The majority of CTE cases express themselves via behavioral and emotional changes such as depression, antisocial behavior, lack of impulse control, and fiscal and legal irresponsibility.
These changes are also keenly seen in FTD cases, wherein the frontal brain lobe, the seat of socialization, emotional intelligence, and rational thinking, deteriorates over time (incidentally, more information on frontal lobe brain function and its loss can be found in Illuminating The Functional Architecture Of The Broken Brain). CTE is also often marked by memory loss and confusion, the central issue in Alzheimer’s Disease. The end result of long-term CTE is a brain that, upon autopsy, shows severe atrophy in several major lobar regions, especially the frontal and temporal lobes. If allowed to progress long enough, CTE can even advance into the hippocampus, the seat of short term and long term memory.
The majority of dementia research has focused solely on Alzheimer’s Disease and, more specifically, the amyloid beta peptide tangles that are often associated with it (more information about Alzheimer’s Disease can be found at Alzheimer Disease and the “Nun Study”). These tangles form the basis of the Amyloid Cascade Hypothesis that states that the accumulation of amyloid beta plaques is the key initiating event in the majority of neurodegenerative diseases, followed by abnormal tau hyperphosphorylation and aggregation into neurofibrillary tangles. More recent findings have been showing that such a model is too simplistic, and that tau hyperphosphorylation is in itself sufficient to result in neurodegeneration (2).
So, what is the actual function of tau, and what makes it so critical in daily cognition? Tau is primarily a neuronal protein that is found in the brain, where it binds to and stabilizes the microtubule assembly of neurons. Microtubules are the cytoskeleton of the neuron and are found extensively in the axon, where action potentials travel from the neuronal soma (body) to the axon terminals, initiating the release of neurotransmitters. When the tau protein is functioning normally and binding microtubules as expected, there are at least three observed effects: neurite outgrowth, axonal transport, and microtubule assembly and stability (3).
Phosphorylation of tau is the predominant mechanism by which its activity is regulated, with the kinases glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (cdk5) being major players in this process. At the other end of the scale are the phosphatases, namely protein phosphatase 2A and 2B (PP2A and PP2B), that remove phosphate groups from the tau protein. Both tau kinases and phosphatases must work in concert for tau protein to function correctly (4).
Much evidence is accumulating that incorrect phosphorylation or hyperphosphorylation of tau results in its malfunction. Such incorrect or hyperphosphorylation can itself be the result of either GSK3β/cdk5 and/or PP2A/PP2A malfunction. However, there is ample evidence that point mutations in the tau protein can also lead to this problem. Also, because the tau mRNA is spliced in different ways to form six tau isoforms in the adult brain, the risk of something going wrong at the transcriptional level is highly likely.
The bottom line of tau malfunction is the following: incorrectly and hyperphosphorylated tau protein dissociates from the neuronal microtubule cytoskeleton, leading to microtubule destabilization. This nonfunctional tau then self-associates and forms paired helical filaments (PHF), which fall out of solution (precipitate) and become visible plaques. Even worse, the nonfunctional tau gains a malfunction; acting like a prion, nonfunctional tau sequesters normally phosphorylated tau proteins, preventing them from binding to microtubules.
Without the aid of functional tau, microtubules become destabilized and incapable of neurite growth and fast axonal transport. PHFs aggregate and neurodegeneration is the result.
There is a clear genetic correlation between nonfunctional tau and neurodegeneration. In a rare and heritable form of frontotemporal dementia with parkinsonism (FTDP-17), a tau mutation on chromosome 17 results in an autosomal dominant form of dementia initiating anywhere between 40 and 60 years of age (5). However, the many sporadic cases of frontotemporal dementia indicate that not all dementia is the result of genetic predisposition. Head trauma and thyroid disease have been found to predispose many patients to sporadic frontotemporal dementia, for example (6). Brain trauma, and especially trauma resulting in unconsciousness, was found to result in a 3.3-fold increase in the future risk of frontotemporal dementia.
Accumulating data on CTE cases implicates brain trauma as the initiating event in a molecular cascade leading to the hyperphosphorylation of tau and resulting dementia. Such a cascade takes years, and sometimes even decades, to unravel brain networks to the point where the victim exhibits altered behavior, depression, confusion, and memory loss- all hallmarks of dementia. What is fascinating is that neurodegeneration, once initiated, does not simply stop at the point of the original injury; instead, the now malfunctioning tau spreads like a virus across the majority of the frontal and temporal area of the brain (7). Sometimes, this prion-like tau reaches into far-lying brain regions such as the hippocampus. If CTE progresses long enough, the patient’s brain exhibits actual physical atrophy, much like the brains of frontotemporal dementia or Alzheimer’s patients.
The scientific question that now remains is, given the central role that tau plays in cognition, what exactly is the underlying cascade of molecular events that unravels it? Do the genetic and non-genetic pathways coincide or differ considerably? Answers to these questions will help determine if dementia is the result of incorrect tau isoform transcription, kinase malfunction, phosphatase loss-of-function, or a combination of all three (or additional) phenomena.
More immediately, however, the delicate balance between tau normalcy and malfunction is heavily implicated in the aforementioned brain injury cases. Tau, the kingpin of cognition, has been found to exact heavy tolls for any insult to its surroundings, tolls including depression, dementia, and even death. In light of CTE being the result of brain trauma, another, and more uncomfortable, question must be asked: should contact sports, and especially football, continue to be played?
1. Pro-Bowl Player’s Suicide Renews Head Trauma Debate, by Nancy Walsh. http://www.medpagetoday.com/Orthopedics/SportsMedicine/25064
2. Small SA and Duff K. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron. 2008 Nov 26;60(4):534-42.
3. Johnson, GVW and Stoothoff, WH. Tau phosphorylation in neuronal cell function and dysfunction. J. Cell Science 117, 5721-29.
4. Stoothoff, WH and Johnson, GVW. Tau phosphorylation: physiological and pathological consequences. Biochimica et Biophysica Acta 1739 (2005) 280-297.
5. Foster NL, Wilhelmsen K, Sima AAF, Jones MZ, D’Amato CJ, Gilman S, Conference Participants. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 1997;41:706-715.
6. S M Rosso, E-J Landweer, M Houterman, L Donker Kaat, C M van Duijn, J C van Swieten. Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective case–control study. J Neurol Neurosurg Psychiatry. 2003 November; 74(11): 1574–1576.
7. Gavett et al. Mild traumatic brain injury: a risk factor for neurodegeneration. Alzheimer’s Research & Therapy 2010, 2:18.
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