Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease
in mitochondria of Tg mice overexpressing ABAD, reinforcing the idea that ABAD links Aβ to mitochondria.
Using in situ hybridisation to mtDNA, immunocytochemistry of COX and morphometry of electron micrographs of biopsy specimens, it was demonstrated that neurons showing increased oxidative damage in AD possess also a striking and significant increase in mtDNA and COX.61,62 Moreover, it was found that much of the mtDNA and COX is localised in the neuronal cytoplasm and, in the case of mtDNA, in vacuoles associated with lipofuscin, whereas morphometric analysis showed that mitochondria are significantly reduced in AD. Interestingly, the cellular expression of COX subunit II and IV is reduced during ageing and these age-related changes are more marked in AD,63
suggesting
observed that the distribution of amyloid plaques is anatomically distinct from the COX-deficient hippocampal pyramidal neurons, and the neurons containing NFT or apoptotic labelling are COX-positive. The authors concluded that COX-deficient, succinate- dehydrogenase-positive hippocampal neurons indicative of high mtDNA mutation load do not appear to be prone to apoptosis or to directly participate in the overproduction of tau or Aβ.64
that ageing is a major risk factor for this disease. However, Cottrell and collaborators64
Recently, we observed that the immunoreactivity of the two mitochondrial markers, lipoic acid and COX, is increased in the cytoplasm of pyramidal neurons in AD compared with control cases.65,66
Altogether these studies indicate a clear involvement of mitochondria dysfunction, oxidative stress and neuronal damage/death during AD evolution.
Conclusions
Of significance, lipoic acid is strongly associated with granular structures, and ultrastructure analysis shows localisation to mitochondria, cytosol and, importantly, in organelles identified as autophagic vacuoles and lipofuscin in AD but not in control cases. COX immunoreactivity was limited to mitochondria and cytosol in both AD and control cases. These data suggest that mitochondria are key targets of increased autophagic degradation in AD.65,66
quantified multiple oxidised bases in nuclear DNA and mtDNA of frontal, parietal and temporal lobes and cerebellum from short post-mortem interval AD brain and age-matched control subjects using gas chromatography/mass spectrometry with selective ion monitoring and stable labelled internal standards. It was found that levels of multiple oxidised bases in AD brain specimens are significantly higher in frontal, parietal and temporal lobes compared with control
Wang et al.67
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Crucial to the task of preventing or potentially reducing neuronal injury in AD is the ability to elucidate the mechanisms that precipitate neuronal degeneration and death. There is overwhelming evidence implicating impaired mitochondria and oxidative damage in AD. The fact that mitochondria are the major sources of energy and ROS in cells placed mitochondria at the centre of interest, and much evidence has accumulated implying that mitochondrial defects play a key role in the pathogenesis of the disease. Alterations in mitochondrial function, increased oxidative stress and neurons dying by apoptosis have been observed in AD. These findings support the idea that mitochondria and oxidative stress may trigger the abnormal onset of neuronal degeneration and death that occur in this disease. n
Paula I Moreira is a Researcher at the Centre for Neuroscience and Cell Biology and a teaching assistant in physiology in the Faculty of Medicine at the University of Coimbra in Portugal. Her research is primarily focused on the impact of neurodegenerative conditions on brain function, with a special focus on bioenergetics. The physiologic process of ageing and the pathological process of diabetes have also been studied as important risk factors for neurodegeneration.
subjects and that mtDNA has approximately 10-fold higher levels of oxidised bases than nuclear DNA. These data are consistent with higher levels of oxidative stress in mitochondria. Furthermore, 8- hydroxyguanosine, a marker of DNA oxidation, is approximately 10-fold higher than other oxidised base adducts in both AD and control subjects. DNA from the temporal lobe shows the most oxidative damage, whereas cerebellum is only slightly affected in AD brains.67 Altogether these results suggest that oxidative damage to mtDNA may contribute to the neurodegeneration of AD. More recently, Baloyannis68 reported that in AD cases mitochondrial pathology correlates substantially with the dystrophic dendrites, the loss of dendritic branches and the pathological alteration of the dendritic spines.
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