Metabolic Alterations In Neurodegenerative Disorders

Metabolic Drivers and Bioenergetic Components of Neurodegenerative Disease summarizes recent developments in intervention trials in neurodegenerative diseases, particularly Alzheimer’s and Parkinson’s, as well as increasing evidence for the overlap between drivers of metabolic and neurodegenerative disease that impact mitochondrial function and bioenergetics, and subsequently cellular function and pathophysiology. Topics covered include Brain Glucose and Ketone Utilization in Brain Ageing and Neurodegenerative Diseases; the Mitochondrial Hypothesis: Dysfunction, Bioenergetic Defects, and the Metabolic Link to Alzheimer’s Disease; the Metabolic Impact on Neuroinflammation and Microglial Modulation in Neurodegenerative Diseases, the Impact of Circadian and Diurnal Rhythms on Cellular Metabolic Function and Neurodegenerative Diseases, and much more. Summarizes the current status of and future research in Alzheimer’s and Parkinson’s diseases Reviews the impact of the metabolic hypothesis on underlying mechanisms of neurodegenerative diseases

Metabolic Syndrome and Neurological Disorders brings together information on the cluster of common pathologies which cause metabolic syndrome - abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension - to provide a comprehensive and cutting edge exploration of the link between metabolic syndrome and neurological disorders. Metabolic syndrome is recognized to play a role in neurological disorders such as stroke, Alzheimer's disease, and depression. For the first time in book form, Metabolic Syndrome and Neurological Disorders covers the molecular mechanisms thought to underlie this mirror relationship, as well as how lifestyle and other factors such as oxidative stress and inflammation may play a role in the disease. Grounded in a series of epidemiological studies of metabolic-cognitive syndrome, this book will be a valuable reference for researchers, dietitians, nutritionists, and physicians.

This book aims to provide a state-of-the-art summary of what is currently known about brain glycogen metabolism, detailing the recent advances in our understanding of why glycogen is so critical for normal brain function. The role of glycogen in cellular neurophysiology remains largely unclear and its specific contribution to the energy demand of brain cells is still elusive.Glycogen is the sole cerebral glucose reserve and is emerging as a fundamental component of brain energy metabolism. Pharmacological or genetic manipulation of glycogen metabolism in the brain impairs memory formation and increases susceptibility to epileptic seizures and cortical spreading depression. Glycogen is also directly implicated in abnormal neuronal excitability and mental retardation that characterize brain disorders like Lafora disease and Pompe disease.

Impairment of energy metabolism is a hallmark of brain aging and several neurodegenerative diseases, such as the Alzheimer’s disease (AD). Age- and disease-related hypometabolism is commonly associated with oxidative stress and they are both regarded as major contributors to the decline in synaptic plasticity and cognition. Neuroinflammatory changes, entailing microglial activation and elevated expression of inflammatory cytokines, also correlate with age-related cognitive decline. It is still under debate whether the mitochondrial dysfunction-induced metabolic deficits or the microglia activation-mediated neuroinflammation is the initiator of the cognitive changes in aging and AD. Nevertheless, multiple lines of evidence support the notion that mitochondrial dysfunction and chronic inflammation exacerbate each other, and these mechanistic diversities have cellular redox dysregulation as a common denominator. This research topic focuses on the role of a metabolic-inflammatory axis encompassing the bioenergetic activity, brain inflammatory responses and their redox regulation in healthy brain aging and neurodegenerative diseases. Dynamic interactions among these systems are reviewed in terms of their causative or in-tandem occurrence and how the systemic environment, –e.g., insulin resistance, diabetes, and systemic inflammation–, impacts on brain function.

There is solid evidence of abnormalities in oxidative / energy metabolism with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. The papers contained in this book are an attempt to move studies in this area to a deeper, more mechanistic level.

It has become evident over the last years that abnormalities in RNA processing play a fundamental part in the pathogenesis of neurodegenerative diseases. Cellular viability depends on proper regulation of RNA metabolism and subsequent protein synthesis, which requires the interplay of many processes including transcription, pre--‐mRNA splicing, mRNA editing as well as mRNA stability, transport and translation. Dysfunction in any of these processes, often caused by mutations in the coding and non--‐ coding RNAs, can be very destructive to the cellular environment and consequently impair neural viability. The result of this RNA toxicity can lead to a toxic gain of function or a loss of function, depending on the nature of the mutation. For example, in repeat expansion disorders, such as the newly discovered hexanucleotide repeat expansion in theC9orf72 gene found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a toxic gain of function leads to the formation of RNA foci and the sequestration of RNA binding proteins (RBPs). This in return leads to a loss of function of those RBPs, which is hypothesized to play a significant part in the disease progression of ALS and FTD. Other toxicities arising from repeat expansions are the formation of RNA foci, bi--‐directional transcription and production of repeat associated non--‐ATG (RAN) translation products. This book will touch upon most of these disease mechanisms triggered by aberrant RNA metabolism and will therefore provide a broad perspective of the role of RNA processing and its dysfunction in a variety of neurodegenerative disorders, including ALS, FTD, Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, myotonic dystrophy and ataxias. The proposed authors are leading scientists in the field and are expected to not only discuss their own work, but to be inclusive of historic as well as late breaking discoveries. The compiled chapters will therefore provide a unique collection of novel studies and hypotheses aimed to describe the consequences of altered RNA processing events and its newest molecular players and pathways.

Numerous studies have established a clear connection between neuronal oxidative stress and several neurodegenerative diseases, with consequential damages to lipids, proteins, nucleic acids, etc. In addition, several modifications indicative of oxidative stress have been described in association with neurons, neurofibrillary tangles and senile plaques in Alzheimer's disease, including advanced glycation end products and free carbonyl oxidation.Oxidative damage and antioxidant responses are now well characterized, but sources of damaging free radicals are yet to be fully understood. Evidences of alteration in metal ions metabolism have been reported in various diseases like Alzheimer's, Wilson, Menkes, Prion, Pick, Huntington disease, epilepsy and other pathological events. Thus, metal ions play a pivotal role in neurodegenerative phenomena.Chelation therapy is still in the early days of its development, but research in this area could lead to new products that could revolutionize treatment. Two international conferences on ?Metals and the Brain: From Neurochemistry to Neurodegeneration? (Padova, Italy, 2000 and Fez, Morocco, 2002) were recently held to discuss the role of metal ions in neurophysiopathology. A third will be held in 2005 in Johannesburg, South Africa.This book follows the same train of thought as those conferences, in order to highlight the unquestionable importance of metal ions in the research on the neurophysiopathology of neurodegenerative diseases. The excellent reputation of the scientists who have contributed to this project ensures the quality of the chapters presented here, and hopefully this will help spur new research initiatives in the field, which is still in its infancy.