Untangling The Role Of Tau In Physiology And Pathology

This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.

Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.

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.

This book is aimed at generating an updated reservoir of scientific endeavors undertaken to unravel the complicated yet intriguing topic of neurodegeneration. Scientists from Europe, USA and India who are experts in the field of neurodegenerative diseases have contributed to this book. This book will help readers gain insight into the recent knowledge obtained from Drosophila model, in understanding the molecular mechanisms underlying neurodegenerative disorders and also unravel novel scopes for therapeutic interventions. Different methodologies available to create humanized fly models that faithfully reflects the pathogenicities associated with particular disorders have been described here. It also includes information on the exciting area of neural stem cells. A brief discussion on neurofibrillary tangles, precedes the elaborate description of lessons learnt from Drosophila about Alzheimer's, Parkinson’s, Spinomuscular Atrophy, Huntington’s diseases, RNA expansion disorders and Hereditary Spastic Paraplegia. We have concluded the book with the use of Drosophila for identifying pharmacological therapies for neurodegenerative disorders. The wide range of topics covered here will not only be relevant for beginners who are new to the concept of the extensive utility of Drosophila as a model to study human disorders; but will also be an important contribution to the scientific community, with an insight into the paradigm shift in our understanding of neurodegenerative disorders. Completed with informative tables and communicative illustrations this book will keep the readers glued and intrigued. We have comprehensively anthologized the lessons learnt on neurodegeneration from Drosophila and have thus provided an insight into the multidimensional aspects of pathogenicities of majority of the neurodegenerative disorders.

Alzheimer’s disease is an increasingly common form of dementia and despite rising interest in discovery of novel treatments and investigation into aetiology, there are no currently approved treatments that directly tackle the causes of the condition. Due to its multifactorial pathogenesis, current treatments are directed against symptoms and even precise diagnosis remains difficult as the majority of cases are diagnosed symptomatically and usually confirmed only by autopsy. Alzheimer’s Disease: Recent Findings in Pathophysiology, Diagnostic and Therapeutic Modalities provides a comprehensive overview from aetiology and neurochemistry to diagnosis, evaluation and management of Alzheimer's disease, and latest therapeutic approaches. Intended to provide an introduction to all aspects of the disease and latest developments, this book is ideal for students, postgraduates and researchers in neurochemistry, neurological drug discovery and Alzheimer’s disease.

A practical guide to perioperative cognitive disorders, the most common complications of anesthesia and surgery in older people.

The functions of the brain that allow us to think, feel, move, and perceive the world are the result of an exchange of information within a network composed of millions of specialized cells called neurons and glia. Neurons use neurotransmitters and other extracellular messengers to communicate with each other, and to constantly update and re-organize their network of connections in a process known as neural plasticity. In order to respond to these extracellular signals, neurons are equipped with specialized receptors that can recognize a single neurotransmitter a bit like a lock would recognize a key. They do this by activating or inhibiting a class of specialized signaling proteins and second messengers. Typically, signaling proteins are themselves organized in networks or pathways in which they activate or inhibit each other in order to integrate the mass of information received by a single cell and to regulate the biological functions of this cell. As we can see, rather than simply being a network of neurons, the brain can be seen as a sort of “Russian doll” in which each neuron is at the same time a part of networks with other neurons and the receptacle of many networks composed of signaling proteins. Two individual genes encode two paralogous signaling proteins: Glycogen Synthase Kinase -3 alpha and beta (GSK-3a, GSK-3b), named for its ability to phosphorylate a key metabolic enzyme of glycogen synthesis, glycogen synthase. This unique “glamour and gloom” protein kinase, has been intriguing many researches for over 30 years by its unusual features, still unknown mechanisms of its activation, its regulation by multiple “key” intracellular pathways, and its capacity to influence the functions of many substrates. Since GSK-3 was discovered, there has been significant progress in elucidating its regulatory roles in the neuron and the structure and functions of the brain. Lithium has been used as a gold standard in the treatment of bipolar disorder for 60 years; and “GSK-3’s renaissance” in psychiatry began with the discovery of GSK-3 as lithium's intracellular target. Since then, GSK3 has been implicated in the pathogenesis of mood disorders, schizophrenia, Alzheimer’s disease, ADHD, multiple sclerosis, Fragile X syndrome and Huntington disease. Connections to these and other diseases has led over the last 10 years to the generation of multiple types of GSK-3 inhibitors as promising therapeutic treatments for the aforementioned pathological conditions. During last couple years new genetic models have been generated, including conventional and conditional mouse models, allowing the discovery of new roles of GSK-3 in the mechanism of neurotransmitter action, neurodevelopment, learning and memory formation, GSK-3’s gene - effect on mouse behavior, and other functions. Thus, GSK-3 has been well-established as an intracellular second messenger for several neurotransmitter systems, and as an important therapeutic target of mood stabilizers, antipsychotics and psychomimetic drugs. The proposed Specific Topic for Frontiers in Neuroscience will be focused on the latest advances from leading laboratories in this area, subdivided into 5 topics: (1) GSK-3 history, mechanism of regulation, substrate specificity and comparison between the brain function of two GSK-3 genes through new animal models and cell biology approaches; (2) role of GSK-3 in neurodevelopment and neuronal structure; (3) involvement of GSK-3 in synaptic functions, learning and memory, and in serotonin and dopamine pathways; (4) role of GSK-3 in neuroinflammation, and application to the pathogenesis of multiple sclerosis, AD, schizophrenia, Fragile X, brain tumors, stroke and bipolar disorder; (5) development of GSK-3 inhibitors and their application in psychiatry, including special discussion about the mechanism of lithium action.