Mitochondrial Dysfunction: Common Final Pathway in Brain Aging and Alzheimer’s Disease—Therapeutic Aspects

Abstract

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.

Firefly luciferase mutants as sensors of proteome stress

“…Aggregates can also interfere with the cellular defense mechanisms by altering protein folding homeostasis (Gidalevitz et al, 2006;Satyal et al, 2000), by blocking proteasome mediated degradation (Bence et al, 2001;Bennett et al, 2005) or by inhibiting autophagy . Other models suggest that the aggregates can engage in aberrant interaction with cellular membranes leading to the formation of membrane pores (Lashuel et al, 2002) or they can disturb cellular ion homeostasis (Quist et al, 2005), may cause mitochondrial dysfunction and oxidative stress (Muller et al, 2010) (Figure 8). Neuronal cell death in diseases like Huntington's disease and Alzheimer's disease can be contributed by both loss-of-function of native active proteins and/or gain-of-function by misfolded proteins.…”

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Failure of ATP synthase could contribute to a decrease in the activity of the entire ETC and impaired ATP production, resulting in possible electron leakage and increased ROS production, suggesting an alternate rationale for the OS seen in AD (10,74). Altered expression of mitochondrial proteins, functional deficits, and lowered activity in different complexes of the ETC are observed in AD (184,281). These changes, coupled with the changes in complex I, III, and IV, may cause electron leakage from the mitochondria to produce ROS.…”

Green Tea Polyphenols Extend the Lifespan of MaleDrosophila melanogasterWhile Impairing Reproductive Fitness

“…suggested to play a role in aging and age-related disorders. [30][31][32][33] It is, therefore, purported that the enhancement of antioxidant enzymes such as SOD, which converts superoxide to H 2 O 2 , and catalase, which converts H 2 O 2 to water and oxygen, may attenuate age-related oxidative damage, thus resulting in the extension of life span. 34.35 We investigated the ability of GTP to enhance these antioxidant enzymes.…”