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.

Methods in Toxicology, Volume 2: Mitochondrial Dysfunction provides a source of methods, techniques, and experimental approaches for studying the role of abnormal mitochondrial function in cell injury. The book discusses the methods for the preparation and basic functional assessment of mitochondria from liver, kidney, muscle, and brain; the methods for assessing mitochondrial dysfunction in vivo and in intact organs; and the structural aspects of mitochondrial dysfunction are addressed. The text also describes chemical detoxification and metabolism as well as specific metabolic reactions that are especially important targets or indicators of damage. The methods for measurement of alterations in fatty acid and phospholipid metabolism and for the analysis and manipulation of oxidative injury and antioxidant systems are also considered. The book further tackles additional methods on mitochondrial energetics and transport processes; approaches for assessing impaired function of mitochondria; and genetic and developmental aspects of mitochondrial disease and toxicology. The text also looks into mitochondrial DNA synthesis, covalent binding to mitochondrial DNA, DNA repair, and mitochondrial dysfunction in the context of developing individuals and cellular differentiation. Microbiologists, toxicologists, biochemists, and molecular pharmacologists will find the book invaluable.

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.

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.

In Alzheimer's disease, neuronal degeneration due to apoptosis has been linked to overexpression and aberrant amyloidogenic processing of the amyloid precursor protein (APP), as well as to bioenergetic defects characterized by deficits in the electron transport chain's cytochrome c oxidase (COX) which leads to the genera ion of radical oxygen species. Inhibition of oxidative energy metabolism increased the amyloidogenic processing of APP, which led to neurotoxicity. Overexpression of APP in cultured normal human muscle fibres caused a specific decrease in COX activity, followed by ultrastructural abnormalities of mitochondria. We have demonstrated, using the yeast two-hybrid system, that APP interacts with COX subunit 1 (COX I), and that this interaction involves the extracellular domain of APP. We demonstrated that APP caused specific deficits in COX activity, induced the production of radical oxygen species and lipid peroxidation, and enhanced neuronal apoptosis. However, anti-oxidant enzyme activity was variable, and probably represented a compensatory reaction to elevated oxygen radicals. To directly interact with COY, APP must be targeted to, and localized in, mitochondria. This possibility was tested with an ' in vitro' mitochondrial import assay which showed that APP is transported to mitochondria in an energy-dependent manner. Furthermore, dual fluorescence microscopy with chimeric APP-green fluorescent protein, and immunoelectron microscopy, demonstrated the presence of endogenous APP and B-amyloid peptide (the neurotoxic cleavage product of APP) in mitochondria of postmortem human brain tissue, with increased levels of B-amyloid peptide in AD brains compared to non-AD brains. (Abstract shortened by UMI.).

This multidisciplinary book includes current research papers and reviews in the areas of basic neuroscience, neural mechanisms underlying neurodegenerative disorders. It further includes new approaches for neuroprotective treatments, clinical, neurobiological and treatment aspects of psychiatric disorders. The book was conceived as a celebration of the professional life and work of Peter Riederer to mark the occasion of his retirement.

Twenty-five years ago, Earl R. Stadtman, PhD discovered that specific enzymes regulating metabolism can be inactivated by oxidation [1]. He later showed that age-related oxidative modification contributes, at least in part, to age-related loss of function of the enzymes [2, 3]. Dr. Stadtman broke the ground for a new field of study to discover how oxidative stress contributes in significant ways to age-related cellular dysfunction and protein accumulation and that oxidation in the aging brain influences Alzheimer’s disease, ischemia-reperfusion injury, amyotrophic lateral sclerosis, and lifespan [4–6]. Today, his research and mentorship have positively influenced the work of hundreds of scientists in this field. We dedicate this book to Dr. Earl R. Stadtman (1912–2008), in celebration of his passion for science and his superior collaborative and mentorship skills. This book is comprised of three sections. The first describes the valuable roles reactive oxygen species (ROS) and reactive nitrogen species (RNS) play in cellular biology. The second section provides an overview of redox imbalance injury with effects on mitochondria, signaling, endoplasmic reticular function, and on aging in general. The third section takes these mechanisms to neurodegenerative disorders and provides a state-of-the-art look at the roles redox imbalances play in age-related susceptibility to disease and in the disease processes. In the first section we attempt to answer a question posed by Dr. Stadtman, ‘‘Why have cells selected reactive oxygen species to regulate cell signaling events’’ [7].

There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.