Special Issue "Tau Protein and Alzheimer’s disease"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 October 2015)

Special Issue Editors

Guest Editor
Prof. Dr. Claude M. Wischik

Division of Applied Medicine, School of Medicine and Dentistry, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Road, Aberdeen AB25 2ZP, UK
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Co-Guest Editor
Dr. Charles Harrington

Division of Applied Medicine, School of Medicine and Dentistry, College of Life Sciences and Medicine, University of Aberdeen, Foresterhill Road, Aberdeen AB25 2ZP, UK
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Published Papers (8 papers)

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Research

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Open AccessCommunication Internalization of the Extracellular Full-Length Tau Inside Neuro2A and Cortical Cells Is Enhanced by Phosphorylation
Biomolecules 2016, 6(3), 36; doi:10.3390/biom6030036
Received: 9 March 2016 / Revised: 4 July 2016 / Accepted: 20 July 2016 / Published: 19 August 2016
Cited by 1 | PDF Full-text (12872 KB) | HTML Full-text | XML Full-text
Abstract
Tau protein is mainly intracellular. However, several studies have demonstrated that full-length Tau can be released into the interstitial fluid of the brain. The physiological or pathological function of this extracellular Tau remains unknown. Moreover, as evidence suggests, extracellular Tau aggregates can be
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Tau protein is mainly intracellular. However, several studies have demonstrated that full-length Tau can be released into the interstitial fluid of the brain. The physiological or pathological function of this extracellular Tau remains unknown. Moreover, as evidence suggests, extracellular Tau aggregates can be internalized by neurons, seeding Tau aggregation. However, much less is known about small species of Tau. In this study, we hypothesized that the status of phosphorylation could alter the internalization of recombinant Tau in Neuro2A and cortical cells. Our preliminary results revealed that the highly phosphorylated form of Tau entered the cells ten times more easily than a low phosphorylated one. This suggests that hyperphosphorylated Tau protein could spread between neurons in pathological conditions such as Alzheimer’s disease. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
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Open AccessArticle Absence of a Role for Phosphorylation in the Tau Pathology of Alzheimer’s Disease
Biomolecules 2016, 6(2), 19; doi:10.3390/biom6020019
Received: 13 December 2015 / Revised: 20 March 2016 / Accepted: 31 March 2016 / Published: 8 April 2016
Cited by 3 | PDF Full-text (2962 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and
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Alzheimer’s disease is characterized by redistribution of the tau protein pool from soluble to aggregated states. Aggregation forms proteolytically stable core polymers restricted to the repeat domain, and this binding interaction has prion-like properties. We have compared the binding properties of tau and tubulin in vitro using a system in which we can measure binding affinities for proteins alternated between solid and aqueous phases. The study reveals that a phase-shifted repeat domain fragment from the Paired Helical Filament core contains all that is required for high affinity tau-tau binding. Unlike tau-tubulin binding, tau-tau binding shows concentration-dependent enhancement in both phase directions due to an avidity effect which permits one molecule to bind to many as the concentration in the opposite phase increases. Phosphorylation of tau inhibits tau-tau binding and tau-tubulin binding to equivalent extents. Tau-tau binding is favoured over tau-tubulin binding by factors in the range 19–41-fold, irrespective of phosphorylation status. A critical requirement for tau to become aggregation-competent is prior binding to a solid-phase substrate, which induces a conformational change in the repeat domain permitting high-affinity binding to occur even if tau is phosphorylated. The endogenous species enabling this nucleation event to occur in vivo remains to be identified. The findings of the study suggest that development of disease-modifying drugs for tauopathies should not target phosphorylation, but rather should target inhibitors of tau-tau binding or inhibitors of the binding interaction with as yet unidentified endogenous polyanionic substrates required to nucleate tau assembly. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
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Review

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Open AccessReview NMR Meets Tau: Insights into Its Function and Pathology
Biomolecules 2016, 6(2), 28; doi:10.3390/biom6020028
Received: 30 March 2016 / Revised: 2 May 2016 / Accepted: 26 May 2016 / Published: 7 June 2016
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Abstract
In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked
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In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked to both aspects. NMR spectroscopy has depicted accurate phosphorylation patterns by different kinases, and its non-destructive character has allowed functional assays with the same samples. Finally, we will discuss other post-translational modifications of Tau and its interaction with other cellular factors in relationship to its (dys)function. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
Open AccessReview Molecular Mechanisms in the Pathogenesis of Alzheimer’s disease and Tauopathies-Prion-Like Seeded Aggregation and Phosphorylation
Biomolecules 2016, 6(2), 24; doi:10.3390/biom6020024
Received: 12 March 2016 / Revised: 19 April 2016 / Accepted: 22 April 2016 / Published: 28 April 2016
Cited by 11 | PDF Full-text (633 KB) | HTML Full-text | XML Full-text
Abstract
Neurofibrillary tau pathology (tangles and threads) and extracellular amyloid-β (Aβ) pathology are defining features of Alzheimer’s disease. For 25 years, most research has focused on the amyloid hypothesis of AD pathogenesis and progression. But, because of failures in clinical trials of Aβ-targeted therapies
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Neurofibrillary tau pathology (tangles and threads) and extracellular amyloid-β (Aβ) pathology are defining features of Alzheimer’s disease. For 25 years, most research has focused on the amyloid hypothesis of AD pathogenesis and progression. But, because of failures in clinical trials of Aβ-targeted therapies and the new concept of prion-like propagation of intracellular abnormal proteins, tau has come back into the spotlight as a candidate therapeutic target in AD. Tau pathologies are found in a range of neurodegenerative disorders, but extensive analyses of pathological tau in diseased brains has demonstrated that the abnormal tau protein in each disease is structurally distinct, supporting the idea that progression of the diverse but characteristic tau pathologies occurs through prion-like seed-dependent aggregation. Therefore, intervention in the conversion of normal tau to abnormal forms and in cell-to-cell transmission of tau may be the key to development of disease-modifying therapies for AD and other dementing disorders. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
Open AccessReview New Features about Tau Function and Dysfunction
Biomolecules 2016, 6(2), 21; doi:10.3390/biom6020021
Received: 29 October 2015 / Revised: 9 March 2016 / Accepted: 13 April 2016 / Published: 19 April 2016
Cited by 13 | PDF Full-text (221 KB) | HTML Full-text | XML Full-text
Abstract
Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a
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Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD). Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
Open AccessReview Nuclear Tau and Its Potential Role in Alzheimer’s Disease
Biomolecules 2016, 6(1), 9; doi:10.3390/biom6010009
Received: 24 November 2015 / Revised: 16 December 2015 / Accepted: 23 December 2015 / Published: 7 January 2016
Cited by 9 | PDF Full-text (934 KB) | HTML Full-text | XML Full-text
Abstract
Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer’s disease (AD). For nearly four decades, research efforts have focused more on tau’s role in physiology and pathology in the context of
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Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer’s disease (AD). For nearly four decades, research efforts have focused more on tau’s role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau’s localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
Open AccessReview Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies
Biomolecules 2016, 6(1), 6; doi:10.3390/biom6010006
Received: 2 November 2015 / Revised: 28 November 2015 / Accepted: 1 December 2015 / Published: 6 January 2016
Cited by 24 | PDF Full-text (3851 KB) | HTML Full-text | XML Full-text
Abstract
Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of
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Abnormal deposition of misprocessed and aggregated proteins is a common final pathway of most neurodegenerative diseases, including Alzheimer’s disease (AD). AD is characterized by the extraneuronal deposition of the amyloid β (Aβ) protein in the form of plaques and the intraneuronal aggregation of the microtubule-associated protein tau in the form of filaments. Based on the biochemically diverse range of pathological tau proteins, a number of approaches have been proposed to develop new potential therapeutics. Here we discuss some of the most promising ones: inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules. We also emphasize the need to achieve a full understanding of the biological roles and post-translational modifications of normal tau, as well as the molecular events responsible for selective neuronal vulnerability to tau pathology and its propagation. It is concluded that answering key questions on the relationship between Aβ and tau pathology should lead to a better understanding of the nature of secondary tauopathies, especially AD, and open new therapeutic targets and strategies. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)
Figures

Open AccessReview Characteristics of Tau and Its Ligands in PET Imaging
Biomolecules 2016, 6(1), 7; doi:10.3390/biom6010007
Received: 3 November 2015 / Revised: 24 December 2015 / Accepted: 28 December 2015 / Published: 6 January 2016
Cited by 18 | PDF Full-text (3669 KB) | HTML Full-text | XML Full-text
Abstract
Tau deposition is one of the neuropathological hallmarks in Alzheimer’s disease as well as in other neurodegenerative disorders called tauopathies. Recent efforts to develop selective tau radiopharmaceuticals have allowed the visualization of tau deposits in vivo. In vivo tau imaging allows the
[...] Read more.
Tau deposition is one of the neuropathological hallmarks in Alzheimer’s disease as well as in other neurodegenerative disorders called tauopathies. Recent efforts to develop selective tau radiopharmaceuticals have allowed the visualization of tau deposits in vivo. In vivo tau imaging allows the assessment of the regional distribution of tau deposits in a single human subject over time for determining the pathophysiology of tau accumulation in aging and neurodegenerative conditions as well as for application in drug discovery of anti-dementia drugs as surrogate markers. However, tau deposits show complicated characteristics because of different isoform composition, histopathology, and ultrastructure in various neurodegenerative conditions. In addition, since tau radiopharmaceuticals possess different chemotype classes, they may show different binding characteristics with heterogeneous tau deposits. In this review, we describe the characteristics of tau deposits and their ligands that have β-sheet binding properties, and the status of tau imaging in clinical studies. Full article
(This article belongs to the Special Issue Tau Protein and Alzheimer’s disease)

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