Cytochrome C Oxidase in Alzheimer's Disease Brain

Wd, Parker; Jk, Parks

doi:10.1212/wnl.45.3.482

Cited by 141 publications

(84 citation statements)

References 10 publications

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“…Our original intent to use Complex III activity as an internal control would have been effective (Barrientos, 2002); Complex I could be used, but it tends to be the most difficult complex to assay and results were not available for every subject. Our Western data, as well as previous literature reports (Parker et al, 1990(Parker et al, , 1994aParker and Parks, 1995), support the contention that Complex IV is catalytically abnormal in AD while protein levels remain normal; it remains unproven what effect that would have on Complex III, if Complex III itself were not also abnormal but subsequently downregulated, or vice versa. While Parker and Parks (1995) characterized a specific catalytic abnormality in Complex IV, the same type of analysis has not been performed on Complex III.…”

Section: Discussionsupporting

confidence: 89%

Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment

et al. 2006

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Mitochondrial abnormalities are found in Alzheimer's disease (AD), but previous reports haven't examined at-risk groups. In subjects with AD, mild cognitive impairment (MCI), and nondemented aged controls, platelet and lymphocyte mitochondria were isolated and analyzed for Complexes I, III, and IV of the electron transport chain. Western blots were used to control for differential enrichment of samples. Results demonstrated significant declines in Complexes III and IV in AD, and a significant decline in Complex IV in MCI. This report confirms mitochondrial deficiencies in AD, extends them to MCI, and suggests they are present at the earliest symptomatic stages of disease.

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Section: Discussionsupporting

confidence: 89%

Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment

et al. 2006

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“…In addition to these disease hallmarks, a consistent pattern of changes in mitochondrial morphology and function is detected in AD at an early stage. For example, there is a decrease in the number of mitochondria in vulnerable neurons accompanied by increase in mitochondrial DNA (mtDNA) and protein in cytoplasm and vacuoles, indicating a greater turnover of mitochondria by autophagy or decreased proteolytic turnover [2]; brain glucose metabolism is decreased [3]; and the activities of both tricarboxylic acid (TCA) cycle enzymes [4] and cytochrome c oxidase (COX) are reduced [5][6][7][8]. Recently it was also shown that the levels of mitochondrial fission/fusion proteins are altered and that mitochondria are redistributed away from axons in pyramidal neurons of AD brain [9,10].…”

Section: Introductionmentioning

confidence: 99%

Dimebon (Latrepirdine) Enhances Mitochondrial Function and Protects Neuronal Cells from Death

Zhang

Hedskog

Petersen

et al. 2010

JAD

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Abstract. Dimebon, a drug currently being evaluated in multiple Phase III Alzheimer's disease trials, has previously been shown to have effects on isolated mitochondria at µM concentrations. Here the effects of nM concentrations of Dimebon on mitochondrial function were investigated both in primary mouse cortical neurons and human neuroblastoma cells (SH-SY5Y). Under non-stress conditions nM concentrations of Dimebon increased succinate dehydrogenase activity (MTT-assay), mitochondrial membrane potential (∆Ψm), and cellular ATP levels. Dimebon treatment had no effect on mitochondria DNA content, implying that mitochondrial biogenesis was not induced. Under stress conditions, mitochondria in Dimebon-treated neurons showed increased resistance to elevated intracellular calcium concentrations, thus, maintaining their ∆Ψm throughout the experiment, in contrast to control neurons, which rapidly lost their ∆Ψm. Moreover, we show that serum-starved differentiated SH-SY5Y cells treated with Dimebon had an increased survival rate as compared to untreated cells. In conclusion, these data demonstrate that Dimebon enhances mitochondrial function both in the absence and presence of stress and Dimebon-treated cells are partially protected to maintain cell viability.

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“…It has been reported that mitochondrial A␤ accumulation impairs neuronal function and, thus, contributes to cellular dysfunction in a transgenic APP mouse model (13). It is noteworthy that in AD at an early stage there is already a reduction in the number of mitochondria (14), the brain glucose metabolism is decreased (15), and the activities of both tricarboxylic acid cycle enzymes (16) and cytochrome c oxidase (COX) are reduced (17)(18)(19)(20). In vitro studies with isolated mitochondria suggest that A␤ 1-42 inhibits COX activity in a copper-dependent manner (21).…”

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confidence: 99%

The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

Petersen

Alikhani²,

Behbahani³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

619

453

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The amyloid ␤-peptide (A␤) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by A␤ and accumulation of A␤ has been detected in mitochondria. Because A␤ is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial A␤ uptake. Our results from rat mitochondria show that A␤ is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed A␤ association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of A␤ to mitochondrial cristae. A similar distribution pattern of A␤ in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for A␤ in mitochondria and demonstrate both in vitro and in vivo that A␤ is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied A␤ can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of A␤, a peptide considered to be of major significance in Alzheimer's disease.Alzheimer disease ͉ protein import ͉ human brain biopsies T he amyloid-␤ peptide (A␤) is produced by regulated intramembrane proteolysis of the A␤ precursor protein (APP) by the sequential cleavage by ␤-and ␥-secretases (1-2). Plaques consisting mainly of aggregated A␤ are detected in the neuropil in aged subjects and in particular in subjects with Alzheimer's disease (AD) (3-5). Recently, it has been argued that it is A␤ oligomers and fibrils that cause toxicity, loss of synapses, and ultimately neuronal death (6-9). The exact mechanisms of how A␤ damages the neurons are still unknown; however, several lines of evidence implicate that A␤ exerts its toxicity intracellularly (10, 11) and point toward a role of mitochondria in this process (12). It has been reported that mitochondrial A␤ accumulation impairs neuronal function and, thus, contributes to cellular dysfunction in a transgenic APP mouse model (13). It is noteworthy that in AD at an early stage there is already a reduction in the number of mitochondria (14), the brain glucose metabolism is decreased (15), and the activities of both tricarboxylic acid cycle enzymes (16) and cytochrome c oxidase (COX) are reduced (17)(18)(19)(20). In vitro studies with isolated mitochondria suggest that A␤ 1-42 inhibits COX activity in a copper-dependent manner (21). Furthermore, mitochondrial A␤-binding alcohol dehydrogenase (ABAD) has been found to be up-regulated in neurons from AD patients (22), and A␤ has been shown to interact with ABAD, resulting in free radical production and neuronal apoptosis. Recently, we have shown that preseque...

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Cytochrome C Oxidase in Alzheimer's Disease Brain

Cited by 141 publications

References 10 publications

Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment

Impaired platelet mitochondrial activity in Alzheimer’s disease and mild cognitive impairment

Dimebon (Latrepirdine) Enhances Mitochondrial Function and Protects Neuronal Cells from Death

The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

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