Oxidative Energy Metabolism In Neurodegenerative Disorders

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.

This book is about the role of both defects in oxidative phosphorylation and oxidative stress in the pathogenesis of neurodegenerative diseases. It describes the relationship between impaired energy metabolism, excytotoxicity and the generation of free radicals. The role of mitochondrial dysfunction in normal aging, and its potential role in the delayed onset of neurodegenerative diseases as well as the result of animal studies using mitochondrial toxins such as MPTP and 3-nitropropionic acid are described. The evidence for both dysfunction and oxidative stress in Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are critically reviewed. Lastly, five different therapeutic approaches to treatment of neurodegenerative diseases are discussed.

Mitochondria have long been the Rodney Dangerfield of cellular organelles. Believed to be the remnants of bacterial infection of eukaryotic cells eons ago, the mitochondrion evolved a symbiotic relationship in which it dutifully served as the efficient source of A TP for cell function. The extraordinary dependence of cells on the energy provided by mito chondrial oxidative metabolism of glucose, especially through critical organs such as the heart and brain, is underlined by the fatal consequences of toxins that interfere with the mitochondrial electron transport system. Consistent with their ancestry, the mitochondria have their own DNA that encodes many but not all of their proteins. The mitochon dria and their genes come from the mother via the ovum since sperm do not possess mitochondria. This extranuclear form of inheritance derived exclusively from the female side has proven to be a powerful tool for tracing the evolution by the number of base substitutions in mtDNA. That mitochondrial gene mutations might be a source of human dis ease became evident a decade ago with the characterization of a group of multisystem disorders, typically involving the nervous system, which are transmitted from mother to child. Specific point mutations in mtDNA have been associated with the different syndromes.

This book is based on an international symposium titled "Cytochrome oxidase in energy metabolism and Alzheimer's disease," held as a satellite to the 27th meeting of the Society for Neuroscience, New Orleans, 1997. The symposium was dedicated in honor of Dr. Margaret T. T. Wong-Riley because, in our opinion, the cytochrome oxidase histo chemical method introduced by Dr. Wong-Riley in 1979 was the most significant break through to map energy metabolism in the entire brain since the 2-deoxyglucose method introduced by Dr. Louis Sokoloff and colleagues in 1977. Both of these metabolic map ping techniques have made monumental contributions to brain research by allowing an integral view of brain activity. They have also developed into various specialized tech niques, including applications to the human brain. One of these new applications, which is described in detail in this book, is the quantitative cytochrome oxidase cytochemical method used to study Alzheimer's disease. The objective of this book is to describe the role of cytochrome oxidase in neuronal metabolism and Alzheimer's disease. Whether genetic or environmental, the pathogenesis of Alzheimer's disease involves a cascade of multiple intracellular events, eventually re sulting in failure of oxidative energy metabolism. Could impairment of cytochrome oxi dase in energy metabolism initiate the degenerative process? Cytochrome oxidase function and dysfunction are discussed in relationship to neuronal energy metabolism, neurodegen eration, and Alzheimer's disease. The book is made up of 10 chapters, divided into three major parts.

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.

The discovery that several major human neurodegenerative diseases are associated with mitochondrial dysfunction has provided new opportunities for a better understanding of these diseases. In this book, major figures in the field offer state-of-the-art reviews of the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of neurodegenerative diseases. Because many of the topics presented overlap with one another, the result is the most comprehensive review of the subject to date. Mitochondria and Free Radicals in Neurodegenerative Diseases begins with a historical overview of the field presented by one of its distinguished founders. The book goes on to supply detailed information on energy metabolism in normal brain function and to explore the role of oxidative damage—which may be a consequence of mitochondrial dysfunction—in the nervous system. Other early chapters focus on energy dysfunction leading to excitotoxic cell damage, the role of mitochondrial toxins in the pathogenesis of animal models of neurodegenerative diseases, and the role of mitochondria in aging. Additional topics include: Neurologic and neuropathologic consequences of mitochondrial disorders The role of mitochondria and oxidative damage in amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, and cerebellar degenerations Using MRI spectroscopy to assess energy defects in patients with neurodegenerative diseases Potential therapies for neurodegenerative diseases The role of glutamate receptor antagonists for therapy Known approaches to improving energy function in mitochondrial disorders Free radical scavengers and other innovative therapeutic approaches Cover image: Three-dimensional reconstruction of an isolated, condensed rat-liver mitochondrion, obtained by electron tomography, courtesy of Dr. Carmen A. Mannella and Wadsworth Center. Reproduced with permission from TiBS (1997) vol. 22, issue 2, pp. 37-38.