Innate Immunity And Neurodegenerative Disorders

Inflammation of the brain in the context of neurodegenerative disorders is an area of intense debate and discussion, not least in terms of its pathogenic significance and the extent to which it drives disease processes and pathology. This inflammation can take several forms including innate responses recruiting microglia, humoral responses involving antibody, complement mediated processes and cellular T-cell activation, of which the role and extent of each may differ between diseases. Whilst some diseases have been more intensely linked to inflammation and long-term degeneration (e.g. MS), more traditional chronic neurodegenerative disorders have been thought of in terms of intrinsic neuronal pathology with a secondary innate response. However, it has been described that microglia activation is an early event of many degenerative disorders and evidence is accumulating that it may play a critical role in actually causing pathology and driving disease processes. If true, this would have major therapeutic implications, but what is the evidence that this is the case? The initial observations by Patrick McGeer’s group of post-mortem tissue from patients with Parkinson’s disease revealed the presence of activated brain microglia and has thus lead to the hypothesis that chronic inflammation could participate to neuronal degenerative processes. The significance of these original observations has only been recently revisited, and the development of more powerful tools to study the brain immune response has certainly contributed to this field of research. Chronic inflammation in the brain can take many forms but of particular interest has been the resident microglia and the role they play in this process. In this context, microglia have often been thought to become activated only after the disease has begun and then to contribute minimally to the degenerative process. Emerging new concepts challenge this view by proposing that microglial senescence, for example, may release the disease process and/or accelerate it. In addition, microglia, once activated, can adopt different phenotypes which can be both pro-inflammatory and pro-repair and may impact not only on the healthy adult neuronal population but on those new neurons derived from neurogenic niches of the adult brain. In this Research Topic, we attempt to explore this by first considering the innate immune responses in the brain and the methods by which they can be studied experimentally and in patients with various neurodegenerative disorders. This sets the scene for then discussing a range of different disorders including Alzheimer’s, Parkinson’s, Huntington’s disease and amyotrophic lateral sclerosis. These papers seek to discuss the evidence for an innate immune response and whether this is beneficial or detrimental, as well as its therapeutic implications.

The last decade has seen an upsurge of information on the role of immune responses in neurodegenerative disorders. In many of these diseases it is still unclear whether the innate and adaptive responses are pathogenic or play a role in repair, and thus understanding their precise roles is key to controlling these diseases by designing immune-therapeutic approaches. The connection between many neurological diseases is the realisation that the immune and nervous systems are inextricable linked, and that perturbations in this delicate balance are involved in many disorders. This has opened up new avenues for therapeutic approaches to treatment of CNS inflammatory and neurodegenerative disorders. Neuroinflammation and CNS Disorders brings together the very latest information on the interactions between the immune system and central nervous system. The first section of the book highlights the basic concepts in the field whilst the second section, the main body of the book, covers the role of the immune response in specific disorders of the central nervous system. Neuroinflammation and CNS Disorders will provide an invaluable guide for both researchers and clinicians working in this complex and dynamic field.

Mitochondria are crucial organelles for any cell type. Mitochondria take responsibility for not only energy production but also regulation of cell death, also called apoptosis; calcium storage; and heat production. Therefore, mitochondrial disease is implicated in the mode of action of many harmful factors for cells such as drugs and environmental contaminants, dysfunction of the oxygen transport system, malnutrition, intense exercise, and genetic variations. This book presents up-to-date knowledge about mitochondrial disease and its complex relation to some diseases such as cardiac failure, cancer, and Alzheimer's and Parkinson's diseases. This book will, therefore, be essential for readers who are interested in life sciences, especially in medicine.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases with rates increasing along with the ageing global population. Despite best efforts, we still do not understand the etiopathogenesis of these diseases and there are no effective disease-modifying treatments. Cognitive deficiencies or motor complications that emerge during AD and PD are thought to be the result of the accumulation of misfolded, aggregate-prone proteins, such as amyloid-? (A?) and tau or ?-synuclein (?-syn), respectively. Growing evidence suggests that prefibrillar oligomers of A? and ?-syn (oA? and o?-syn) are key contributors to the progression of these diseases. The progressive accumulation of these proteins leads to a gradual spread of pathology throughout interconnected brain regions, but the mechanisms by which this spreading occurs are still largely unknown. Neuroinflammation has been recognised as an important contributor to neurodegenerative disease. It is hypothesised that a pro-inflammatory environment initiated by the innate immune system, either through activation from A? itself or indirectly through neuronal injury signals in AD. These phenomena are thought to either cause or accelerate AD, such that an anti-inflammatory approach may be neuroprotective. In paper I, we investigated whether different inflammatory environments affected the transfer of oA? between neuron-like cells, in addition to investigating inter- and intracellular protein changes. This study demonstrated that an anti-inflammatory environment reduces the transfer of oA? between cells. We also provide evidence that these cells begin to take on the “phenotype” of the inflammatory milieu, while also demonstrating that the expression profile of endosomal/lysosomal and protein trafficking proteins is altered during these conditions. Small extracellular vesicles called exosomes, which are key players in cell to cell communication, have been proposed to play an influential role in spreading neurodegenerative proteins between cells. Exosomes are small membranous vesicles that are formed by the inward budding of multivesicular bodies (MVBs). These MVBs can then merge with the plasma membrane to be released into the extracellular environment as vesicles, which serve as vehicles for transferring proteins, lipids, and mRNAs between cells. The ESCRT-dependent pathway is the most understood mechanism underlying exosome biogenesis. However, exosomes can also be formed through ESCRT-independent pathways, including through the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2), which produces ceramide. Paper II investigated whether exosomes formed through an ESCRT-independent pathway plays a significant role in the transfer of o?-syn between neuron-like cells. As oxidative stress is a common feature in PD brains, which in turn dysregulates nSMase2 activity, we also tested our model under hypoxic conditions. Inhibition of nSMase2 significantly reduced the transfer of o?-syn between cells but also resulted in decreased ?-syn aggregation. Hypoxia did not influence o?-syn transfer, however, it significantly dysregulated the sphingolipid composition, which may be important for ?-syn binding to exosomes and exosome communication. During AD and PD, there is a noted reduction in the effectiveness of autophagy, a process critical to cellular proteostasis. Recent studies have uncovered shared regulatory mechanisms of exosome biogenesis and autophagy, suggesting that they are closely linked. Previous findings have shown that inhibition of autophagy in AD mice mediates A? trafficking through altering the secretion of A? in MVBs. To further study this effect, we investigated the interplay between autophagy and exosome secretion using ATG7 knock-out x APPNL-F knock-in AD mice in paper III. These autophagy-deficient AD mice had a reduced extracellular A? plaque load, but increased intracellular A?, which was found to be assembled into higher-ordered assemblies. While exosomal secretion was dysregulated in these mice, the amount of A? packaged into the exosomes was unchanged. Lastly, one of the biggest challenges in developing effective treatments for AD is the lack of early diagnosis of living patients. As the connection between exosomes and the spread of neurodegenerative proteins is still relatively new, there remains a diagnostic potential to be explored with exosomes. Paper IV aimed to develop a new diagnostic assay to detect oA? in exosomes isolated from human cerebrospinal fluid. Although exosomal oA? was readily detected in some of these samples, the assay’s sensitivity requires additional optimisation before it can be further validated for the clinic. In summary, the studies presented in this thesis have furthered our understanding of how inflammation, autophagy, and exosomes contribute to the intercellular transmission of AD and PD associated proteins. We have shown that an anti-inflammatory approach may slow down the progression of AD through reducing the transfer of oA? between cells. We also provide novel findings relating to the biogenesis of exosomes, which in turn affected the ability of exosomes to transmit neurodegenerative proteins between cells, and their association with autophagic processes. Finally, we have investigated the feasibility of exosomes as an early AD diagnostic marker. This work has helped to elucidate some of the mechanisms underlying the progression of neurodegenerative diseases, which may be useful targets for the investigation of new therapeutic avenues.

The book focuses on various aspects and properties of innate immunity, whose deep understanding is integral for safeguarding the human race from further loss of resources and economies due to innate immune response-mediated diseases. Throughout this book, we examine the individual mechanisms by which the innate immune response acts to protect the host from pathogenic infectious agents and other non-communicable diseases. Written by experts in the field, the volume discusses the significance of macrophages in infectious disease, tumor metabolism, and muscular disorders. Chapters cover such topics as the fate of differentiated macrophages and the molecular pathways that are important for the pathologic role of macrophages.

The Molecular Immunology of Neurological Diseases provides a comprehensive review of current updates in molecular immunogenetics of different neurological diseases. Readers will learn about the role of immune cells and their modulation strategies to help in the development of therapeutic approaches for both acute and chronic neurodegenerative disorders. There is no other book available on the topic. It has long been thought that the brain is an immune-privilege organ with very limited immune response. However recent studies have made clear that both systemic 'brain' and peripheral 'blood' immune cell responses play key roles in determining brain pathology in neurodegenerative disorders. This book summarizes the role of immune cell activation in the central nervous system microenvironment in acute and chronic neurodegenerative disorders. In addition, it discusses the key role of immune cells and their modulation strategies for the development of current therapeutic approaches. Discusses the molecular immunogenetics of different neurological diseases Covers strategies for the development of therapeutic approaches Encompasses both acute and chronic neurogenerative disorders Describes the molecular pathogenesis of viral genes in various diseases Features chapters on migraine, muscular dystrophy and cancer

Our understanding of the complex innate immune response is increasing rapidly. Its role in the protection against viral or bacterial pathogens is essential for the survival of an organism. However, it is equally important to avoid unregulated inflammation because innate immune responses can cause or promote chronic autoinflammatory diseases such as gout, atherosclerosis, type 2 diabetes or certain aspects of the metabolic syndrome. In this book leading international experts in the field of innate immunity share their findings, define the ‚state of the art‘ in this field and evaluate how insight into the molecular basis of these diseases could help in the design of new therapies. A tremendous amount of work on the innate immune response has been done over the last fifteen years, culminating in the 2011 Nobel Prize in Physiology/Medicine awarded for the discoveries of Toll genes in immunity in flies, membrane-bound Toll-like receptors in mammals, and dendritic cells as initiators of adaptive immunity.