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: 10.76). 06/2001; 101(5):518-24. DOI: 10.1007/s004010000330
Source: PubMed


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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    • "Alternative splicing produces an N-terminal region that may have zero, one, or two variable polypeptide segments while the microtubule-binding region may contain either three or four repeat sequences with moderate homology. Roughly equal amounts of 3R and 4R isoforms are found in fibrils isolated from the brains of patients with AD [12], chronic traumatic encephalopathy [13], and tangle-only dementia [14]. The 4R isoforms are predominant in fibrils found in progressive supranuclear palsy [15], corticobasal degeneration [16], and agyrophilic grain disease brain tissue [17] [18], while Pick's disease inclusions are predominantly composed of 3R isoforms [19]. "
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    ABSTRACT: Tauopathies encompass a broad family of neurodegenerative diseases, including Alzheimer's disease, which are characterized by the fibrillization of the microtubule-associated tau protein. The normal function of tau is to stabilize and promote the assembly of microtubules in neuronal axons. Sequestration of tau into amyloid fibrils results in destabilization of the microtubule network and may contribute to disease progression. As tau is an intracellular protein and proteins do not passively cross cell membranes, tau fibril formation has been assumed to occur spontaneously within individual cells. However, recent evidence suggests that tau shares several characteristics with prions, which propagate through the brain by protein-protein interactions in the interstitial space; these characteristics include conformational templating of native tau into disease-associated fibrils and intercellular fibril propagation. Tau adopts diverse fibril structures, or strains, which have been shown to self-propagate in the presence of monomeric recombinant tau protein. Exogenous tau fibrils induce misfolding of native tau in both cell culture and animal models, causing strain-dependent cellular dysfunction and differential patterns of neuropathology. Tau fibers have also been found recently in patient samples or models of several diseases not formerly identified as tauopathies, including chronic traumatic encephalopathy, Parkinson's disease, and Huntington's disease, suggesting a common underlying mechanism for neurodegenerative diseases. The possibility that tauopathies and other neurodegenerative diseases involve prion-like mechanisms has implications for studies designed to understand disease pathogenesis and for the development of therapies, which may be devised to impede tau strain propagation and intercellular transmission, allowing clearance of tau fibrils and potentially halting or reversing disease progression.
    Full-text · Chapter · Jan 2015
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    • "Following the description of the ‘punch drunk’ symptom spectrum in boxers by Martland in 1928 [1] and motor deficits and mental confusion, termed dementia pugilistica, by Millspaugh in 1937 [54], Corsellis et al in 1973 published the neuropathological findings of 15 boxers and concluded that dementia pugilistica was a neuropathologically distinct disorder despite its similarities to AD [29]. The NFTs in CTE and AD are biochemically the same, containing both 3R and 4R tau [55]. However, tau pathologies in CTE tend to cluster around blood vessels, locate in the depths of the sulci and in the superficial cortical layers, are patchy and irregularly distributed and Aβ deposits are relatively scanty [4,56,57]. "
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    ABSTRACT: We report the case of a 75-year-old ex-professional boxer who developed diplopia and eye movement abnormalities in his 60's followed by memory impairment, low mood and recurrent falls. Examination shortly before death revealed hypomimia, dysarthria, vertical supranuclear gaze palsy and impaired postural reflexes. Pathological examination demonstrated 4-repeat tau neuronal and glial lesions, including tufted astrocytes, consistent with a diagnosis of progressive supranuclear palsy. In addition, neurofibrillary tangles composed of mixed 3-repeat and 4-repeat tau and astrocytic tangles in a distribution highly suggestive of chronic traumatic encephalopathy were observed together with limbic TDP-43 pathology. Possible mechanisms for the co-occurrence of these two tau pathologies are discussed.
    Full-text · Article · Feb 2014
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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.
    Full-text · Article · May 2012 · Brain Imaging and Behavior
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