Mitochondrial Dysfunction and Oxidative Stress in Alzheimer's Disease

Mitochondria are the power plants of the cell, responsible for constructing chemical energy store molecules, adenosine triphosphate (ATP). With age, mitochondria become increasingly dysfunction, performing less useful work while generating more reactive oxygen species (ROS) capable of damaging cellular machinery via inappropriate oxidative reactions. Raised levels of ROS, or oxidative stress, are just as much a feature of aging as mitochondrial dysfunction. Many researchers see oxidative damage to cells as important in age-related disease, but it is far from settled as to whether or not this mechanism is in fact important in comparison to others, such as, for example, reduced levels of the ATP needed to power cellular processes.

The exact mechanisms underlying Alzheimer's disease (AD) remain unclear despite comprehensive attempts to understand its pathophysiology. The most prominent theory postulates that, in AD, tau and amyloid-β negatively affect neuronal cells by compromising energy supply and the antioxidant response, causing mitochondrial and synaptic dysfunction. Neuronal activity is highly energy-dependent, and neurons are particularly sensitive to disruption in mitochondrial function. In addition, mitochondria produce cellular energy (adenosine triphosphate; ATP) and are also involved in many processes that are important for the life and death of the cell, including the control of second messenger levels, such as calcium ions (Ca2+) and reactive oxygen species (ROS).

Importantly, mitochondrial dysfunction contributes to reduced ATP production, Ca2+ dyshomeostasis, and ROS generation. Alterations in mitochondrial dynamics and mitophagy occur in early-stage AD, but the underlying mechanisms are poorly understood. Thus, studies elucidating the mechanisms of mitochondrial abnormalities in AD will facilitate a greater understanding of the pathogenesis of this neurodegenerative disease and potentially contribute to the advancement of therapeutic strategies to protect synaptic activity and subsequent cognitive function. Here, we review studies that suggest a role of mitochondrial dysfunction and the consequent ROS production in AD pathology and provide a context to explain current and future therapeutic approaches. We suggest that improving mitochondrial function should be considered an important therapeutic intervention against AD.


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