Tau Biology (Advances in Experimental Medicine and Biology, 1184)

Tau filaments with distinct morphologies and/or isoform compositions underlie a large number of human neurodegenerative diseases. Their formation is important, because dominantly inherited mutations in MAPT, the tau gene, cause frontotemporal dementia with abundant filamentous tau inclusions. Assembly of tau may begin in a specific region of the brain, from where it spreads to other areas. It remains to be seen if the molecular species underlying tau aggregate-mediated neurodegeneration and propagation are the same or different. In the brains of mice transgenic for human mutant P301S tau, small tau filaments are the predominant seed-competent species. It has been suggested that different conformers of assembled tau may give rise to different human tauopathies, but until recently, it was not possible to study this directly. Electron cryo-microscopy can now be used to determine high-resolution structures of amyloid filaments from human brain. Paired helical and straight tau filaments of Alzheimer's disease are ultrastructural polymorphs. Each filament core is composed of two identical protofilaments extending from G273/304-E380 (in the numbering of the 441 amino acid isoform of human tau), which adopt a combined cross-β/β-helix structure. They comprise the ends of the first or second microtubule-binding repeat (R1 or R2), the whole of R3 and R4, as well as 12 amino acids after R4. By contrast, the core of the narrow filament of Pick's disease consists of a single protofilament extending from K254-F378 of 3R tau, which adopts a cross-β structure. It comprises the last 21 amino acids of R1, all of R3 and R4, as well as 10 amino acids after R4. Wide tau filaments of Pick's disease, which are in the minority, consist of two narrow filaments packed against each other. The tau filament folds of Alzheimer's and Pick's diseases appear to be conserved between different cases of disease. These findings show that filamentous tau adopts one fold in Alzheimer's disease and a different fold in Pick's disease, establishing the existence of distinct conformers. Preface Contents Part I: Structure and Role of the Tau Molecule 1: Ordered Assembly of Tau Protein and Neurodegeneration Introduction Tau Protein Tau Isoforms Tau Assemblies Genetics of MAPT Neurodegeneration and Propagation High-Resolution Structures of Tau Filaments from Alzheimer’s Disease High-Resolution Structures of Tau Filaments from Pick’s Disease Conclusion References 2: Structure of NFT: Biochemical Approach Introduction Tau Protein Tau in AD Brain Solubility of NFTs and PHFs Biochemical Approaches to PHF-Tau in AD Brains Protein-Chemical Approach to PHF-Tau Attempts to Recapitulate the Abnormal Phosphorylation of Tau Pathological Tau Proteins in Various Neurological Diseases Significance of Tau Phosphorylation Molecular Mechanisms of Tau Aggregation and NFT Formation Conclusions References 3: Nuclear Magnetic Resonance Spectroscopy Insights into Tau Structure in Solution: Impact of Post-translational Modifications Introduction Tau: A Disordered Protein with Local Secondary Structure A Disordered Protein: Tau’s Global Fold Impact of Phosphorylation on Tau Structure Tau prolyl cis/trans isomerization Conclusions References 4: Regulation of Tau Homeostasis and Toxicity by Acetylation Introduction Posttranslational Modifications of Tau Tau Acetylation in Neurodegenerative Disease The Effect of Acetylation on Toxic Tau Species The Effect of Acetylation on Tau Localization and Synaptic Plasticity Acetylated Tau Promotes Memory Loss Targeting Tau Acetylation as Potential Therapeutic Strategy References 5: Tau Clearance Mechanisms The Proteasome Tau Degradation by the 20S Proteasome Tau Degradation by the 26S Proteasome Autophagy Tau Degradation by Autophagy Tau Clearance by Chaperone-Mediated Autophagy (CMA) and Microautophagy Summary References 6: Mechanisms of Axonal Sorting of Tau and Influence of the Axon Initial Segment on Tau Cell Polarity Tau Is an Axonally Targeted Microtubule Associated Protein in the Central Nervous System Sorting of Tau During Neuronal Development Proposed Sorting Mechanisms of Tau The TDB Within the AIS Regulates Tau Transit into the Axon Efficiency of the Tau Diffusion Barrier Depends on the Composition of the AIS Modulation of AIS Plasticity by Tau Expression and Phosphorylation Conclusion References Part II: Tau Localization and Function 7: Tau and Axonal Transport Misregulation in Tauopathies Introduction Tau Protein and Disease Axonal Transport Axonal Degeneration in Tauopathies Tau-Based Effects on Fast Axonal Transport Tau and Regulatory Signaling Pathways for Fast Axonal Transport Tau May Physically Interfere with Kinesin Binding to Microtubules Tau Isoforms Differentially Affect Fast Axonal Transport Other Mechanisms of Fast Axonal Transport Regulation by Tau Conclusion References 8: Presynaptic Pathophysiology Encoded in Different Domains of Tau – Hyper-Versus Hypoexcitability? Introduction Results Discussion References 9: Synaptic Localisation of Tau Introduction Synaptic Localisation of Tau Tau Binds to Synaptic Vesicles Post-Translational Modifications of Tau Affect Synaptic Function Structural Consequences of Aggregated Tau Functional Impacts of Synaptic Localisation of Tau Impact of Tau on Neuronal Activity and Neuronal Circuitry Impact on Neuronal Tau Release Conclusions References 10: The Role of Tau in the Post-synapse Introduction Localization of Tau: Axon vs. Dendrite How Does Tau Affect Synaptic Function? Phosphorylated Tau at the Synapse and Functional Consequences Tau-Mediated Synapse Weakening and Readout of AD Pathology References 11: Tau Secretion Introduction Trans-Synaptic Spread Way Exo-Synaptic Spread Pathway Extracellular Tau Secretory Pathway Vesicular Mediated Secretory Pathway Microvesicles Exosomes Tunneling Nanotubes (TNTs) Species of Tau That Are Secreted The Regulation on Tau Secretion Role of Phosphorylation on Tau Secretion Role of Truncation on Tau Secretion Role of Mutations on Tau Secretion Concluding Remarks References 12: Emerging Connections Between Tau and Nucleic Acids Introduction Tau and DNA Connections Tau-DNA Complex Formation Tau Sequences Involved in DNA Binding DNA Sequences Targeted by Tau Tau and the Maintenance of Genome Integrity DNA Protection Chromatin Organization Pericentromeric Heterochromatin Perinucleolar Heterochromatin and rDNA Genes Genomic Instability in Tauopathies Transposable Elements Aneuploidy Tau and RNA Connections Tau-RNA Interaction RNA Binding Proteins Conclusion References 13: Tau Interacting Proteins: Gaining Insight into the Roles of Tau in Health and Disease Tauopathies Position Tau as a Crucial Protein in Health and Disease The Structure of Protein Tau as a Target for Protein-Protein Interactions Tau:Tau Binding and Tau Aggregation Tau Interactions with Cytoskeletal Proteins Tau and Tubulins: The Microtubule Associated Protein Tau Tau and Actin Cytoskeleton Tau Interactions Inducing Post-Translational Modifications Tau Phosphorylation Other Post-Translational Modifications: Acetylation, Glycosylation, Glycation, Ubiquitination, ... Tau Interactions in the Nucleus Tau Interacts with Synaptic Proteins and Affects Synaptic Function Tau Affects Presynaptic Function, through Binding with Presynaptic Proteins Tau Binds to Postsynaptically Localized Proteins Tau and Proteins Identified in GWAS Tau and Pathologically Aggregating Proteins in Neurodegenerative Disorders Conclusion References Part III: Tau and Disease-Related Proteins 14: Relationship Between Tau, β Amyloid and α-Synuclein Pathologies Frequencies Increase with Age Mixed Pathology vs Mixed Dementia Clinical Implications of Mixed Dementia Neuropathological Burden of Mixed Dementia Putative Synergistic Relationships Between Pathological Proteins HP-T and Aβ in AD HP-T and α-Synuclein Aβ and α-Synuclein HP-T, Aβ, and α-Synuclein – A Toxic Triad? Potential Mechanisms for Interaction Direct Interactions Indirect Interactions Stratification for Clinical Trials References 15: Associations Between APOE Variants, Tau and α-Synuclein Introduction APOE and the Gene Product Apolipoprotein E APOE Variants and the Risk of Tauopathy and Synucleinopathy Evidence from Clinical Studies Linking Apolipoprotein E to Tau and α-Synuclein Fluid Levels Brain Imaging-Based Evidence Linking Apolipoprotein E to Tau and α-Synuclein Cell and Molecular Observations Proposing Associations Between APOE, Tau and α-Synuclein Conclusions References 16: Amyloid-β and Tau at the Crossroads of Alzheimer’s Disease Introduction Alzheimer’s Disease Introduction (History) Neuropathological Features of AD Amyloid Plaques Neurofibrillary Tangles The Genetic Basis of AD and the Amyloid Cascade Hypothesis The Correlations of Amyloid-β and AD Development Amyloid-β Is Unlikely to Drive AD Development Alone Tau Biology and Tau Pathogenesis Amyloid-β Deposition Influences Tau Pathology Amyloid-β Deposition Favors Tau Pathology At the Crossroads of AD Other Pathophysiological Mechanisms That Contribute to AD Concluding Remarks References Part IV: Tauopathies; Pathology, Drivers, and Marker 17: Myotonic Dystrophy: an RNA Toxic Gain of Function Tauopathy? Dystrophia Myotonica: an RNA Gain of Toxic Function Disease A Multisystemic Neuromuscular Disease with Cognitive Dysfunctions Brain Lesions in Myotonic Dystrophy DM1 a Tau Missplicing Tauopahty Diagnostic and Therapeutic Perspective References 18: Tau PET Imaging Introduction Discovery of a Selective Imaging Probe for Tau Pathologies Utility of Tau PET Imaging Demonstrated by Clinical Assessments Development of Next-Generation Tau PET Probes Conclusions References 19: Tau Accumulation and Network Breakdown in Alzheimer’s Disease Introduction Spatial Distribution Pattern of Tau Retention in AD Resting State Networks (RSNs) Relationship Between Tau Retention and RSN Changes in AD Hub Vulnerability in AD Relationship Between Tau Retention and Structural Network Changes in AD Conclusions References 20: Stress and the Etiopathogenesis of Alzheimer’s Disease and Depression Introduction Stress: A Physiological Tug-of-War – From Adaptive to Maladaptive Responses Mechanisms and Consequences of GC Action in the Brain Stress, Glucocorticoids and Neural Plasticity Chronic Stress: Etiopathogenic Role and Mechanisms in AD Consideration Regarding How Chronic Stress and High GC Levels May Contribute to AD Pathology RNA-Binding Proteins and Stress Granules Facilitate Stress-Induced Tau Pathology Tau and Its Malfunction in Stress-Related Brain Pathology: Beyond Alzheimer’s Disease Summary/Conclusions References 21: Tau, Diabetes and Insulin Overview on Tau and Tauopathies Physiology of Insulin Peripheral Insulin Insulin Biosynthesis Insulin Secretion Insulin Signaling Insulin Physiological Functions Insulin in the Brain Origin of Brain Insulin Brain Insulin Receptors Brain Insulin Physiological Functions Pathophysiology of Insulin Functions: Diabetes Mellitus Type 1 Diabetes Type 2 Diabetes Diabetes Mellitus, Tau Pathology and AD T1D, Tau Pathology and AD In Humans In Animal Models T2D, Tau Pathology and AD In Humans In Animal Models Brain Insulin Resistance and Tau Pathology: A Vicious Circle? Brain Insulin Resistance in AD Patients Consequences of Brain Insulin Resistance for Cognition, Longevity, and Metabolism What Is the Trigger for Brain Insulin Resistance in AD? Impact of Insulin Resistance on Tau Lesions Therapeutic Considerations Intranasal Insulin Diabetic Drugs: Peroxisome Proliferator-Activated Receptor-γ Agonists, Metformin, GLP-1, Amylin and Future Drugs Could Anti-Tau Immunotherapy Impact on Brain Insulin Sensitivity? References Part V: Tau Aggregation, and Propagation 22: Top-Down Projections Direct the Gradual Progression of Alzheimer-Related Tau Pathology Throughout the Neocortex Introduction Fundamental Organization of the Neocortex and of Cortico-Cortical Connections Cortico-Cortical Bottom-Up and Top-Down Connectivities in the Neocortex Involvement of Cortico-Cortical Projection Neurons and Their Target Cells in the sAD Process Morphological and Abnormal Tau Changes in Target Cells of Top-Down Connectivities Late-Maturing Top-Down Neurons and Their Target Cells Develop the Earliest Tau Changes. Do They Deliver Directives for Slowing the Pathological Process? References 23: Tau Prion-Like Propagation: State of the Art and Current Challenges Tau Prion-Like Propagation, State of the Art Transmissibility of Tau Pathology, Tau Seeding? Neuron-to-Neuron Transfer of Tau Is Tau Transferred from One Cell to the Other? Routes of Cell-to-Cell Transfer Existence of “Strains” of Tau Aggregates Tau Prion-Like Propagation, Challenges and Future Directions Using More Sporadic Tauopathies Models Tau Propagation, Physiological Versus Pathological Mechanisms Precisely Identify the Kinetics of Tau Life Cycle Events Identify Good Therapeutic Strategies Understand the Regional Patterns, the Cell Vulnerabilities Conclusions References 24: Tau Condensates Introduction Membraneless Organelles Coacervation Tau Droplets The Necessity for Cofactors in Tau Droplet Formation References 25: Liquid-Liquid Phase Separation of Tau Protein in Neurobiology and Pathology States of Tau in the Cell Monomeric (or Dimeric) Soluble Tau Oligomeric and Aggregated States of Tau Liquid and Gel-Like Phases of Tau Drivers of Tau Liquid-Liquid Phase Separation Introduction to Protein Phase Separation Tau Protein Domains in LLPS Protein Concentration Critical for Tau LLPS Phosphorylation of Tau Frontotemporal Dementia Mutations RNA and Polyanions Phase Transition from Tau Liquid Condensates into Aggregates Maturation of Condensed Liquid Tau Phases Emerging of Tau Aggregates from Condensates Potential Roles for Tau LLPS in Neurodegenerative Diseases Ignition of Tau Aggregation by Liquid-Liquid Phase Separation Tau Protein Propagation Through Condensation in the Brain? Condensed Tau and Microtubules Tubulin Co-condensation with Tau Nucleates Microtubules Liquid Tau Phases on Microtubules Methods Used to Study Tau Protein Condensation Conclusion and Outlook References 26: The Pathophysiology of Tau and Stress Granules in Disease Introduction Dysfunction of RNA Binding Proteins in Neurodegenerative Disorders RNA Binding Proteins Mediate Disease Through Stress Granules The Biology of Stress Granules and the Translational Stress Response Phase Transition and the Role of Protein Aggregation in the Biology of SGs Tau and Stress Granules Tau Is Sorted to the Somatodendritic Domain in Stress Tau Regulates Stress Granules Tau Colocalizes with RNA Binding Proteins in Disease Tau Oligomers Mediate Interactions with RNA Binding Proteins A Model for the Interactions of Tau in Stress and with RNA Binding Proteins Therapeutic Approaches Based on Modulating SGs and the Translational Stress Response Conclusion References 27: Tau Oligomers Prediction of Non-fibrillar Aggregates of Tau Protein Tau Oligomer as an Intermediate Species of Tau Filament Various Types of Non-filamentous Tau Aggregates Tau Oligomer Detection Methods EM and Oligomer Antibodies Tau Oligomerization Enhancers, Blockers, and the Toxic Mechanism Conclusion References 28: Experimental Models of Tauopathy – From Mechanisms to Therapies Introduction – The Concept of ‘Tauopathy’ Approaches to Model Tauopathy in Animals Comparative Analysis of Tauopathy Models Insight into Pathomechanisms From Mechanisms to Therapeutic Interventions Is There a Future for Animal Models of Tauopathies? References 29: Cerebrospinal Fluid and Plasma Tau as a Biomarker for Brain Tauopathy Introduction Definite Biomarker for AD Systemic Review and Meta-Analysis Differential Diagnosis and Prediction for Onset of AD ADNI and DIAN Study Demonstrated Signature of AD Prospective Study for Prediction of MCI and Dementia Due to AD Standardization and Newly Developed Assay Technology Origin of CSF Tau and pTau Association Between CSF Biomarkers and Newly Developing Tau Neuroimaging Plasma Phosphorylated Tau as Possible Biomarker for AD Recommendation in the Diagnostic Evaluation of MCI and Dementia References 30: Dementia Therapy Targeting Tau Tau Silencing Tau Alternative Splicing Acetylation and Phosphorylation Tau Metabolism Microtubule Stabilizers Anti-Aggregating Agents Immunotherapy Brain/Body as a Whole References "This book presents essential studies and cutting-edge research results on tau, which is attracting increasing interest as a target for the treatment of Alzheimer's disease. Tau is well known as a microtubule-associated protein that is predominantly localized in the axons of neurons. In various forms of brain disease, neuronal loss occurs, with deposition of hyperphosphorylated tau in the remaining neurons. Important questions remain regarding the way in which tau forms hyperphosphorylated and fibrillar deposits in neurons, and whether tau aggregation represents the toxic pathway leading to neuronal death. With the help of new technologies, researchers are now solving these long-standing questions. In this book, readers will find the latest expert knowledge on all aspects of tau biology, including the structure and role of the tau molecule, tau localization and function, the pathology, drivers, and markers of tauopathies, tau aggregation, and treatments targeting tau. Tau Biology will be an invaluable source of information and fresh ideas for those involved in the development of more effective therapies and for all who seek a better understanding of the biology of the aging brain." -- Prové de l'editor