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

Department of Pharmacology, Biocenter, University of Frankfurt, Max-von Laue-Strasse 9, 60438, Frankfurt, Germany.
Molecular Neurobiology (Impact Factor: 5.14). 06/2010; 41(2-3):159-71. DOI: 10.1007/s12035-010-8141-5
Source: PubMed


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.

13 Reads
  • Source
    • "It has been well established that mitochondrial DNA accumulates mutations with aging [61]. A decrease in the mitochondrial antioxidant superoxide dismutase (MnSOD) has also been found in the cerebrovasculature with increasing age [62]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to investigate the effect of exercise training on age-induced microvascular alterations in the brain. Additionally, the association with the protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) was also assessed. Male Wistar rats were divided into four groups: sedentary-young (SE-Young, n = 5), sedentary aged (SE-Aged, n = 8), immersed-aged (IM-Aged, n = 5), and exercise trained-aged (ET-Aged, 60 minutes/day and 5 days/week for 8 weeks, n = 8) rats. The MAPs of all aged groups, SE-Aged, IM-Aged, and ET-Aged, were significantly higher than that of the SE-Young group. The regional cerebral blood flow (rCBF) in the SE-Aged and IM-Aged was significantly decreased as compared to SE-Young groups. However, rCBF of ET-Aged group was significantly higher than that in the IM-Aged group (P < 0.05). Moreover, the percentage of capillary vascularity (%CV) and the levels of VEGF and eNOS in the ET-Aged group were significantly increased compared to the IM-Aged group (P < 0.05). These results imply that exercise training could improve age-induced microvascular changes and hypoperfusion closely associated with the upregulation of VEGF and eNOS.
    04/2014; 2014(9):230791. DOI:10.1155/2014/230791
  • Source
    • "The β-amyloid protein itself and other lesion-associated proteins have been reported to cause oxidative damage to neurons [16]. Mitochondrial dysfunction in AD could cause an increased generation of free radicals, and damage the major cell components, including DNA, protein and lipid [17], [18], [19], [20], [21], [22], [23]. Isoprostanes, as a marker of lipid peroxidation, were increased in the brain of AD animal models [24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Serum uric acid (UA) could exert neuro-protective effects against Alzheimer's disease (AD) via its antioxidant capacities. Many studies investigated serum UA levels in AD patients, but to date, results from these observational studies are conflicting. We conducted a meta-analysis to compare serum UA levels between AD patients and healthy controls by the random-effects model. Studies were identified by searching PubMed, ISI Web of Science, EMBASE, and the Cochrane library databases from 1966 through July 2013 using the Medical Subject Headings and keywords without restriction in languages. Only case-control studies were included if they had data on serum UA levels in AD patients and healthy controls. Begg's funnel plot and Egger's regression test were applied to assess the potential publication bias. Sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. A total of 11 studies met the inclusion criteria including 2708 participants were abstracted. Serum UA levels were not significantly different in AD patients compared to healthy controls (standardized mean difference (SMD) = -0.50; 95% confidence interval (CI): -1.23 to 0.22). Little evidence of publication bias was observed. Sensitivity analyses showed that the combined SMD was consistent every time omitting any one study, except only one study which greatly influenced the overall results. Meta-regression showed that year of publication, race, sample size, and mean age were not significant sources of heterogeneity. Our meta-analysis of case-control studies suggests that serum UA levels do not differ significantly in AD patients, but there may be a trend toward decreased UA in AD after an appropriate interpretation. More well-designed investigations are needed to demonstrate the potential change of serum UA levels in AD patients.
    PLoS ONE 04/2014; 9(4):e94084. DOI:10.1371/journal.pone.0094084 · 3.23 Impact Factor
  • Source
    • "In other words, physiological levels of ROS can be dealt with by the insect's powerful enzymatic and non-enzymatic detoxification routes. However, mitochondrial dysfunction is observed in AD and this may be exacerbated with age37; therefore it is possible that ROS generated as a consequence of this mitochondrial dysfunction overwhelms cellular detoxification pathways. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The strongest risk factor for developing Alzheimer's Disease (AD) is age. Here, we study the relationship between ageing and AD using a systems biology approach that employs a Drosophila (fruitfly) model of AD in which the flies overexpress the human Aβ42 peptide. We identified 712 genes that are differentially expressed between control and Aβ-expressing flies. We further divided these genes according to how they change over the animal's lifetime and discovered that the AD-related gene expression signature is age-independent. We have identified a number of differentially expressed pathways that are likely to play an important role in the disease, including oxidative stress and innate immunity. In particular, we uncovered two new modifiers of the Aβ phenotype, namely Sod3 and PGRP-SC1b.
    Scientific Reports 12/2013; 3:3512. DOI:10.1038/srep03512 · 5.58 Impact Factor
Show more