Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer's disease.
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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ABSTRACT: Neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the abnormal aggregation of a small number of intracellular proteins, with tau and α-synuclein being the most commonly affected. Until recently, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. It is now believed that protein aggregates form in a small number of brain cells, from which they propagate intercellularly through templated recruitment, reminiscent of the mechanisms by which prions spread through the nervous system.Current Neurology and Neuroscience Reports 11/2014; 14(11):495. DOI:10.1007/s11910-014-0495-z · 3.67 Impact Factor
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ABSTRACT: Intracellular tau inclusions are a pathological hallmark of several neurodegenerative diseases, collectively known as the tauopathies. They include Alzheimer's disease, tangle-only dementia, Pick's disease, argyrophilic grain disease, chronic traumatic encephalopathy, progressive supranuclear palsy and corticobasal degeneration. Tau pathology appears to spread through intercellular propagation, requiring the formation of assembled ″prion-like″species. Several cell and animal models have been described that recapitulate aspects of this phenomenon. However, the molecular characteristics of seed-competent tau remain unclear. Here, we have used a cell model to understand the relationships between tau structure/phosphorylation and seeding by aggregated tau species from the brains of mice transgenic for human mutant P301S tau and full-length aggregated recombinant P301S tau. Deletion of motifs 275VQIINK280 and 306VQIVYK311 abolished the seeding activity of recombinant full-length tau, suggesting that its aggregation was necessary for seeding. We describe conformational differences between native and synthetic tau aggregates that may account for the higher seeding activity of native assembled tau. When added to aggregated tau seeds from the brains of mice transgenic for P301S tau, soluble recombinant tau aggregated and acquired the molecular properties of aggregated tau from transgenic mouse brain. We show that seeding is conferred by aggregated tau that enters cells through macropinocytosis and seeds the assembly of endogenous tau into filaments. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.Journal of Biological Chemistry 11/2014; 290(2). DOI:10.1074/jbc.M114.589309 · 4.60 Impact Factor
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ABSTRACT: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with head trauma. Although initially believed to affect only boxers, the at-risk population has expanded to encompass a much wider demographic, including American football players, hockey players, wrestlers, and military veterans. This expansion has garnered considerable media attention and public concern for the potential neurodegenerative effects of head trauma. The main aim of this systematic review is to give a complete overview of the common findings and risk factors for CTE as well as the status quo regarding the incidence and prevalence of CTE. This systematic review was performed using PubMed and MEDLINE and includes all neuropathologically confirmed cases of CTE in the medical literature to date, from the first published case in 1954 to August 1, 2013 (n = 153). The demographics, including the primary source of mTBI (mild Traumatic Brain Injury), age and cause of death, ApoE genotype, and history of substance abuse, when listed, were obtained from each case report. The demographics of American football players found to have CTE are also presented separately in order to highlight the most prevalent group of CTE cases reported in recent years. These 153 case reports of CTE represent the largest collection to date. We found that a history of mTBI was the only risk factor consistently associated with CTE. In addition, we found no relationships between CTE and age of death or abnormal ApoE allele. Suicide and the presence of premorbid dementia was not strongly associated with CTE. We conclude that the incidence of CTE remains unknown due to the lack of large, longitudinal studies. Furthermore, the neuropathological and clinical findings related to CTE overlap with many common neurodegenerative diseases. Our review reveals significant limitations of the current CTE case reporting and questions the widespread existence of CTE in contact sports.PLoS ONE 01/2015; 10(2):e0117338. DOI:10.1371/journal.pone.0117338 · 3.53 Impact Factor