Chapter Seven - Mitochondrial Dysfunction: Cause and Consequence of Alzheimer's Disease

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Abstract

The etiology of common, nonfamiliar late-onset Alzheimer's disease (LOAD) is only partly understood and seems to be extremely complex including many genetic and environmental factors. The most important environmental risk factor to develop LOAD is aging itself. Aging and LOAD are considered to be strongly linked to mitochondrial dysfunction and enhanced oxidative stress. In this review, we focus on the interaction between mitochondrial dysfunction in aging especially on defects of the respiratory chain of the oxidative phosphorylation system resulting in enhanced oxidative stress and the interplay between aging-associated mitochondrial defects and LOAD-associated mitochondrial failure. The deleterious effects of the two hallmarks of LOAD, amyloid beta, and hyperphosphorylated tau, on mitochondrial function, movement, and morphology are described as well as the toxic effects of the most relevant genetic risk factor of LOAD, the apolipoprotein E4 allele. Finally, the review provides an overview about drugs and nutritional ingredients which improve mitochondrial function or/and act as antioxidants and discusses their potential role in the treatment of LOAD.

Section snippets

Brain Aging: The Role of OXPHOS and ROS

Cells in the central nervous system are affected by aging and react to aging by increasing amounts of reactive oxygen species (ROS), perturbed energy homeostasis, altered calcium signaling, accumulation of damaged proteins, lesions of their DNA on the molecular level, impaired function of signaling mechanisms, and altered gene expression at the cellular level.1 The cell organelles playing the major role in the aging process are the mitochondria, due to their central role in producing ATP as the

Mitochondrial Dysfunction in Alzheimer's Disease

Increasing evidence suggests an important role of mitochondrial dysfunction and oxidative stress in the pathogenesis of many aging-related neurodegenerative diseases, especially Alzheimer's disease (AD).4, 18, 24, 25, 26, 27, 28, 29, 30 Late-onset Alzheimer's disease (LOAD) is a progressive disorder that leads to dementia and affects approximately 10% of the population older than 65 years of age. In contrast to familiar AD (FAD; only affecting 1% of all AD cases worldwide) which is caused by

Aβ and Tau—A Deleterious Duo for Mitochondrial Function

The toxic effect of Aβ on mitochondrial function could be confirmed by several groups in different neuronal cell models as well as in different AD animal models.29, 35 Mainly oligomeric, intracellular Aβ seems to be the toxic species which impairs mitochondrial membrane potential (MMP) and reduces ATP levels.10, 56 When tracing mitochondrial dysfunction at the level of the respiratory chain, complex IV dysfunction seems to be specifically mediated by Aβ which progressively accumulates in

Mitochondrial-Derived ROS Induce Aβ Generation—Focus on Complexes I and III

Several lines of evidence suggest that elevated ROS production might initiate toxic APP processing and thereby trigger toxic Aβ generation. The group of Tabaton showed during the last years that oxidative stress in the form of HNE or H2O2 leads to enhanced Aβ production in cell models.93, 94 In addition, recent data suggest that complex I-derived ROS contribute to amyloidogenic APP processing.27 In cell and animal models, complex I dysfunction induced by functional or genetically mediated

Interplay Between Aging and AD: The Balance Between Synergistic Dysfunction and Functional Compensation

In LOAD, the slow process of brain degeneration begins decades before clinical symptoms appear around midlife.29 Several factors synergistically lead to reduced energy metabolism and enhanced reactive oxygen species (ROS) production. Enhanced oxidative stress in “normal brain aging” is an important factor, due to age-related alterations in ROS producing (for example, complex I defects) or ROS detoxifyng (antioxidant enzymes) mechanisms. Moreover, around midlife, normal “low-level” Aβ production

Pharmacological Strategies to Improve Mitochondrial Function

While the concept of Aβ- and tau-induced mitochondrial dysfunction in AD has received substantial support over the last decade, improving mitochondrial function as a target for new drug development has not. Until recently, scientific interest was mostly focused on drugs leading to reduced Aβ load. However, as several disease-modifying compounds failed to show clinical effectiveness in AD trials.90 Therefore, improving mitochondrial dysfunction might be a promising concept to treat LOAD24, 26

Antioxidants, Flavonoids, Polyphenols, and Ginkgo

Several antioxidants have a long history as possible treatments for AD and even have been and are used in this context. Initially mainly vitamin E or vitamin C or the combination of both has been investigated. While both at high concentrations definitively show antioxidant properties in vitro and in vivo, their therapeutical benefit to improve or even prevent age-related cognitive impairment in AD is still under discussion.23, 144

Another important class of naturally accruing antioxidants are

Metabolic Enhancer

While in many cases there is a substantial overlap between antioxidant and mitochondria-protecting properties, it is important to note that both do not share the same mechanism and several compounds show significant mitochondrial protection without having antioxidant or radical scavenging properties. A drug which has been extensively characterized in this respect is the metabolic enhancer piracetam,112, 134, 135, 156 which shows no antioxidant properties but exhibits pronounced mitochondrial

Dimebon

For the old Russian antiallergic drug dimebon several findings suggested positive effects of dimebon on impaired cognitive functions in AD.142 In most AD animal models, dimebon improved Aβ pathology and improved cognition.137, 157 Only in five FAD mice, dimebon showed no effect on Aβ pathology and behavior.138 However, its efficacy to treat AD is highly discussed due to negative clinical trials. Its molecular mechanism of action is still a matter of debate.143 Recent publications reported

Conclusion and Further Perspective

Impaired mitochondrial metabolism associated with respiratory chain dysfunction and the oxidative stress is considered to be a major pathological mechanism in a number of neurodegenerative diseases including AD. In contrast to Aβ plaques and tau tangles seen in the late stage of AD, mitochondrial dysfunction, and oxidative stress are two early events in the pathology of AD cumulating with aging-associated changes in mitochondrial function, morphology, dynamics, and oxidative stress. Aβ-mediated

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