Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease--therapeutic aspects.
As a fully differentiated organ, our brain is very sensitive to cumulative oxidative damage of proteins, lipids, and DNA occurring during normal aging because of its high energy metabolism and the relative low activity of antioxidative defense mechanisms. As a major consequence, perturbations of energy metabolism including mitochondrial dysfunction, alterations of signaling mechanisms and of gene expression culminate in functional deficits. With the increasing average life span of humans, age-related cognitive disorders such as Alzheimer's disease (AD) are a major health concern in our society. Age-related mitochondrial dysfunction underlies most neurodegenerative diseases, where it is potentiated by disease-specific factors. AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. In this review, we focus on findings in AD animal and cell models indicating that these histopathological alterations induce functional deficits of the respiratory chain complexes and therefore consecutively result in mitochondrial dysfunction and oxidative stress. These parameters lead synergistically with the alterations of the brain aging process to typical signs of neurodegeneration in the later state of the disease, including synaptic dysfunction, loss of synapses and neurites, and finally neuronal loss. We suggest that mitochondrial protection and subsequent reduction of oxidative stress are important targets for prevention and long-term treatment of early stages of AD.
Müller
Walter E
WE
Department of Pharmacology, Biocenter, University of Frankfurt, Max-von Laue-Strasse 9, 60438, Frankfurt, Germany. W.E.Mueller@em.uni-frankfurt.de
Eckert
Anne
A
Kurz
Christopher
C
Eckert
Gunter Peter
GP
Leuner
Kristina
K
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*
D000975:Antioxidants
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