Bioenergetics, aging and neurodegenerative diseases

Abstract

The first part of the book describes normal neuronal metabolism, particularly in respect to energy metabolism. The main energy metabolism of neurons is in the mitochondrial generation of ATP, the latter being obtained also from glycolysis, but to a much lesser extent. The role of neurotransmitters, trophic factors, calcium and growth factors is discussed. The second part contains data on the normal aging of neurons and the decline of energy metabolism in aging cells. Data are discussed which indicate that aging cells are subject to increasing oxidative stress due to insufficient antioxidant defences. During aging, increasing amounts of active oxygen species and oxygen radicals are produced within the cell, which damage cellular macromolecules with the resulting structural and biochemical deterioration. A kind of pathologic positive feedback does occur, which further damages the cell's organizational structure and the energy producing enzymatic machinery. The ultimate outcome of these processes is cell damage and death. A similar sequence of events is taking place in the course of Alzheimer's disease and other neurodegenerative syndromes. The pathomechanism of Alzheimer's disease and other neurodegenerative diseases is described and discussed in the third part of the book. It is proposed that a final common pathway in the development of both aging and neurodegenerative diseases is the hypometabolism with energetic insufficiency and a devastating oxidative stress. The neuropathology of Alzheimer's disease can be explained in most cases by a decline in cellular ATP available for normal functioning of the neurons. Decreased ATP levels are the cause of aberrant protein conformation and aberrant intraneuronal transport of structural proteins and organelles. The oxidative stress accompanying the hypometabolism causes irreversible damage to the neuron's DNA and proteins and leads to cytomembrane lipids' peroxidation. A positive feedback between the decreased metabolism and oxygen stress on the one hand, and structural changes in the cell on the other, leads to irreversible damage to the neurons with consequent neuropathology and cell death. The discussed pathomechanism of aging and neurodegenerative diseases may allow a new approach to the treatment of these diseases. Such new approaches are suggested and discussed.