Chapter Seven - Mitochondrial Dysfunction: Cause and Consequence of Alzheimer's Disease
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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2021, Chinese Chemical LettersOlesoxime improves cerebral mitochondrial dysfunction and enhances Aβ levels in preclinical models of Alzheimer's disease
2020, Experimental NeurologyCitation Excerpt :This fairly new therapeutic target is characterized by defects in the activity/function of important respiratory chain enzymes, the formation of reactive oxidative species (ROS), induction of apoptosis, and changes in mitochondrial biogenesis as well as dynamics. ( Friedland-Leuner et al., 2014; Muller et al., 2010; Stockburger et al., 2018; Swerdlow and Khan, 2009). Swerdlow and co-workers were the first who proposed this concept in the “mitochondrial cascade hypothesis” (Swerdlow and Khan, 2004; Swerdlow et al., 2014).
Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease
2019, Free Radical Biology and MedicineCitation Excerpt :Among various tissues, the brain is particularly vulnerable to oxidative stress and susceptible to lipid peroxidation because of its high lipid and polyunsaturated fatty acid contents as well as high oxygen consumption coupled with an inherent lower antioxidant capability [60,61]. The progression of oxidative stress in AD is associated with mitochondrial dysfunction, leading to superoxide overproduction resulting in synaptic damage [62,63]. We have previously reported that Aβ is accumulated predominantly in the mitochondrial compartment at the early stage of disease in APdE9 mice, and that mitochondrial dysfunction may be involved in the mechanism of oxidative stress increase before the onset of AD [64].