Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA.
Acta Neuropathologica (Impact Factor: 9.78). 06/2001; 101(5):518-24. DOI: 10.1007/s004010000330
Source: PubMed

ABSTRACT Insights into mechanisms of familial Alzheimer's disease (AD) caused by genetic mutations have emerged rapidly compared to sporadic AD. Indeed, despite identification of several sporadic AD risk factors, it remains enigmatic how or why they predispose to neurodegenerative disease. For example, traumatic brain injury (TBI) predisposes to AD, and recurrent TBI in career boxers may cause a progressive memory disorder associated with AD-like brain pathology known as dementia pugilistica (DP). Although the reasons for this are unknown, repeated TBI may cause DP by mechanisms similar to those involved in AD. To investigate this possibility, we compared the molecular profile of tau pathologies in DP with those in AD and showed that the same tau epitopes map to filamentous tau inclusions in AD and DP brains, while the abnormal tau proteins isolated from DP brains are indistinguishable from the six abnormally phosphorylated brain tau isoforms in AD brains. Thus, these data suggest that recurrent TBI may cause DP by activating pathological mechanisms similar to those that cause brain degeneration due to accumulations of filamentous tau lesions in AD, and similar, albeit attenuated, activation of these processes by a single TBI may increase susceptibility to sporadic AD decades after the event.

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    • "Tau-immunoreactive NFTs may be particularly dense in the hippocampus, amygdala , entorhinal cortex and olfactory bulbs in advanced stages of the disease (Gavett et al. 2011a; McKee et al. 2009). Although the specific tau isoforms found in CTE are indistinguishable from AD (Schmidt et al. 2001), the irregular nature of tau deposition and the perivascular clustering of tau-immunoreactive abnormalities at the depth of the sulci are unique to CTE and distinguish it from other tauopathies , including AD (McKee et al. 2009). In addition, the density of the NFTs and GTs is often far greater in CTE than in other tauopathies (Gavett et al. 2011a). "
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    ABSTRACT: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused, at least in part, by repetitive brain trauma, including concussive and subconcussive injuries. It is thought to result in executive dysfunction, memory impairment, depression and suicidality, apathy, poor impulse control, and eventually dementia. Beyond repetitive brain trauma, the risk factors for CTE remain unknown. CTE is neuropathologically characterized by aggregation and accumulation of hyperphosphorylated tau and TDP-43. Recent postmortem findings indicate that CTE may affect a broader population than was initially conceptualized, particularly contact sport athletes and those with a history of military combat. Given the large population that could potentially be affected, CTE may represent an important issue in public health. Although there has been greater public awareness brought to the condition in recent years, there are still many research questions that remain. Thus far, CTE can only be diagnosed post-mortem. Current research efforts are focused on the creation of clinical diagnostic criteria, finding objective biomarkers for CTE, and understanding the additional risk factors and underlying mechanism that causes the disease. This review examines research to date and suggests future directions worthy of exploration.
    Brain Imaging and Behavior 05/2012; 6(2):244-54. DOI:10.1007/s11682-012-9164-5 · 4.60 Impact Factor
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    • "In advanced cases, tau-immunoreactive inclusions in the limbic and paralimbic regions, diencephalon, brainstem, and subcortical white matter have also been reported (Stern et al. 2011). The specific soluble and insoluble tau isoforms that are found in the NFTs in CTE are indistinguishable from NFTs in AD (Schmidt et al. 2001) and the ratio of tau isoforms with four versus three microtubule binding repeats is approximately 1 in both diseases (McKee et al. 2009). In the hippocampus and entorhinal cortex, the NFT distribution is comparable to that observed in AD, with numerous NFTs in the CA1 field, subiculum and layer II and V of the entorhinal cortex (Hof et al. 1992). "
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    ABSTRACT: Chronic traumatic encephalopathy (CTE) is a form of neurodegeneration that results from repetitive brain trauma. Not surprisingly, CTE has been linked to participation in contact sports such as boxing, hockey and American football. In American football getting "dinged" equates to moments of dizziness, confusion, or grogginess that can follow a blow to the head. There are approximately 100,000 to 300,000 concussive episodes occurring in the game of American football alone each year. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, sets off a cascade of events that result in neurodegenerative changes highlighted by accumulations of hyperphosphorylated tau and neuronal TAR DNA-binding protein-43 (TDP-43). Symptoms of CTE may begin years or decades later and include a progressive decline of memory, as well as depression, poor impulse control, suicidal behavior, and, eventually, dementia similar to Alzheimer's disease. In some individuals, CTE is also associated with motor neuron disease similar to amyotrophic lateral sclerosis. Given the millions of athletes participating in contact sports that involve repetitive brain trauma, CTE represents an important public health issue. In this review, we discuss recent advances in understanding the etiology of CTE. It is now known that those instances of mild concussion or "dings" that we may have previously not noticed could very well be causing progressive neurodegenerative damage to a player's brain. In the future, focused and intensive study of the risk factors could potentially uncover methods to prevent and treat this disease.
    SpringerPlus 03/2012; 1:2. DOI:10.1186/2193-1801-1-2
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    • "In fact, AD in humans can only be fully confirmed post-mortem via the presence of extracellular senile plaques, which are abnormal amyloid β (Aβ) protein deposits, and abnormal tau protein aggregation in specific brain regions (Price et al., 1991). The tau protein is an important functional component of the cytoskeleton in healthy neurons, but it is also a predominant component of neurofibrillary plaques found in AD and dementia pugilistica (Schmidt et al., 2001). Therefore, the development of abnormal tau protein pathology is a potential molecular link between TBI and dementia. "
    Brain Injury - Pathogenesis, Monitoring, Recovery and Management, 12/2011; , ISBN: 978-953-51-0265-6
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