PMC:2944646 / 5429-8797
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2944646","sourcedb":"PMC","sourceid":"2944646","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2944646","text":"Mitochondrial Dysfunction and Oxidative Stress in Brain Aging and Alzheimer Disease\nLike other differentiated tissues, the central nervous system is profoundly affected by aging and reacts to aging by a decline of several physiological abilities including sensory, motor, emotional, or cognitive functions (Sastre et al., 2000; Floyd and Hensley, 2002; Balaban et al., 2005; Mattson and Magnus, 2006; Onyango et al., 2010). Aging brain cells experience increasing amounts of oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins, lesions in their nucleic acids and are characterized by impaired function of signaling mechanisms and altered gene expression. These changes were significantly exacerbated in neurodegenerative disorders and amplified in vulnerable neuronal populations be disease related processes such as accumulation of damaged proteins, e.g., Amyloid-beta (Aß) levels in Alzheimer's disease (AD) (Cleary et al., 2005; Haass and Selkoe, 2007; Selkoe, 2008; Querfurth and LaFerla, 2010). Beside the described dysfunctions, mitochondrial perturbations are strongly associated with aging. Mitochondria play a central role in producing ATP as the central source of cellular energy and are critical regulators of programmed cell death during aging (Sastre et al., 2000; Atamna, 2004; Balaban et al., 2005; Schuessel et al., 2006). Mitochondrial function becomes less efficient during brain aging including decreased activities of complex I and to a lesser content of complex IV of the respiratory chain, which in turn leads to enhanced ROS production, reduced Ca2+ buffering capacity, and accumulation of mitochondrial DNA (mtDNA) mutations (reviews for this topic (Mattson, 2007; Mattson et al., 2008).\nAbnormalities in mitochondrial function and oxidative stress are also relevant for the pathogenesis of Alzheimer's disease (AD) (Hauptmann et al., 2006; Anandatheerthavarada and Devi, 2007; Leuner et al., 2007; Moreira et al., 2007; Reddy and Beal, 2008). In the brain of AD patients, defective energy metabolism and early defects in glucose utilization were observed already many years before (Munch et al., 1998). Moreover, the AD brain is specifically marked by accumulation of the misfolded proteins Aß and hyperphosphorylated tau, both contributing together with aging-related deficits to severe neurodegenerative alterations, such as the loss of synapses and neurons, atrophy, and the selective depletion of neurotransmitter systems (e.g., acetylcholine) in the hippocampus and cerebral cortex (Haass and Selkoe, 2007; Querfurth and LaFerla, 2010). At the mitochondrial level, complex I and complex IV seem to be specifically affected, where tau pathology mainly impairs complex I activity, and Aß complex IV activity (Eckert et al., 2008; Hauptmann et al., 2009; Rhein et al., 2009). One of the earliest changes observed in AD is synaptic failure which already starts in patients with mild cognitive impairment (MCI) and manifests during the disease process (Selkoe, 2002). Mitochondria are key players in synaptic plasticity providing the necessary energy (Mattson et al., 2008). The observed mitochondrial deficits result in enhanced oxidative stress. Importantly, mitochondrial dysfunction and reduced bioenergetics occur early in pathogenesis and precede the development of plaque formation (Hauptmann et al., 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