Reduced platelet cytochrome c oxidase activity in Alzheimer's disease

Parker, W. Davis; Mahr, Nicolas; Filley, Christopher M.; Parks, Jason C.; Hughes, Dempsey L; Young, Douglas A.; Cullum, C. Munro

doi:10.1212/wnl.44.6.1086

Cited by 197 publications

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“…The platelet activities of Complexes II-IV and citrate synthase were examined by Parker et al (1994a), and they reported a significant reduction only in Complex IV in AD patients. Complex III was decreased slightly in their study, and other groups finding ETC Complex IV deficiency did not also examine Complex III (Bosetti et al, 2002;Cardoso et al, 2004a).…”

Section: Discussionmentioning

confidence: 99%

“…The internal normalization of the activity results was to be accomplished by the ratio of complex I and IV to complex III, as recommended by Barrientos (2002), given that no significant difference had been found previously in platelet Complex III (Parker et al, 1994a). The unanticipated finding of a significant difference across groups in Complex III activity precluded normalizing subjects by that internal ratio.…”

Section: Methodsmentioning

confidence: 99%

“…Parker's original finding of reduced platelet Complex IV activity in AD has been replicated (Parker et al, 1994a;Bosetti et al, 2002;Cardoso et al, 2004a), yet the role of mitochondrial abnormalities remains largely undefined. Amyloid-β (Aβ), the protein that makes up the amyloid plaques in the brain of AD patients, has been shown to interact directly with mitochondria and inhibit Complex IV activity (Crouch et al, 2005) and induce oxidative stress (Lustbader et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…A number of studies reported a reduction in COX activity and an increase in oxidative stress in brain tissues and platelets from AD patients (7)(8)(9)(10). More recently, the associations of heteroplasmic mutations in the mtDNA control region and point mutations in mtDNA-encoded COX subunits with sporadic AD cases were reported (11,12), supporting the contribution of mtDNA mutations and COX reduction to the development of AD.…”

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confidence: 95%

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

Fukui¹,

Díaz²,

Garcia³

et al. 2007

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

168

140

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Defects in the mitochondrial cytochrome c oxidase (COX) have been associated with Alzheimer's Disease, in which the agedependent accumulation of ␤-amyloid plays an important role in synaptic dysfunction and neurodegeneration. To test the possibility that age-dependent decline in the mitochondrial respiratory function, especially COX activity, may participate in the formation and accumulation of ␤-amyloid, we generated mice expressing mutant amyloid precursor protein and mutant presenilin 1 in a neuron-specific COX-deficient background. A neuron-specific COXdeficient mouse was generated by the Cre-loxP system, in which the COX10 gene was deleted by a CamKII␣ promoter-driven Crerecombinase. COX10 is a farnesyltransferase involved in the biosynthesis of heme a, required for COX assembly and function. These KO mice showed an age-dependent COX deficiency in the cerebral cortex and hippocampus. Surprisingly, COX10 KO mice exhibited significantly fewer amyloid plaques in their brains compared with the COX-competent transgenic mice. This reduction in amyloid plaques in the KO mouse was accompanied by a reduction in A␤42 level, ␤-secretase activity, and oxidative damage. Likewise, production of reactive oxygen species from cells with partial COX activity was not elevated. Collectively, our results suggest that, contrary to previous models, a defect in neuronal COX does not increase oxidative damage nor predispose for the formation of amyloidgenic amyloid precursor protein fragments. mitochondria ͉ oxidative phosphorylation ͉ neurodegeneration A lzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, characterized by progressive brain atrophy/neuronal death that results in cognitive and memory impairment. Starting from the identification of genes responsible for familial AD, which is now known to constitute only Ͻ5% of total AD incidence, an ''amyloid hypothesis'' has been built up during the past few decades, and an enormous effort has been devoted to understand the toxic mechanism of ␤-amyloid (A␤), which forms extracellular amyloid plaques and is generated by a successive proteolytic cleavage of amyloid precursor protein (APP) by ␤-secretase and a ␥-secretase complex containing presenilins (1). Although it is not clear to what extent different A␤ species (soluble oligomers, insoluble aggregates, extracellular species, or intracellular species) contribute to neurodegeneration in vivo, recent studies demonstrated the toxicity of diverse A␤ species in vitro, in situ, and in vivo, confirming the importance of age-dependent A␤ accumulation in AD pathogenesis (2-5).Recently, age-dependent accumulation of mutations in mitochondrial DNA (mtDNA) and resulting increase in oxidative stress and impairment in mitochondrial respiratory chain, especially complex IV or cytochrome c oxidase (COX), gained attention as potential factors that could participate in the onset of sporadic AD (6). A number of studies reported a reduction in COX activity and an increase in oxidative stress in brain tissues and plate...

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“…Some factors contributing to AD include ␤-amyloid precursor protein (APP) mutations, ApoE genotype, transmembrane proteins S182 and STM2, reduced glucose transport, excitotoxins, head trauma, and deficiencies in mitochondrial cytochrome c oxidase (COX or complex IV) activity (Parker et al, 1990b(Parker et al, , 1994aParker, 1991;Chandrasekaran et al, 1992;Kish et al, 1992;Mutisya et al, 1994;Mattson, 1995;Yanker, 1996;Davis et al, 1997). The idea of a mitochondrial component to neurodegenerative diseases is not new, and it has also been proposed for Parkinson's disease and Guam Parkinsonism / Dementia Complex (Parker et al, 1990a(Parker et al, , 1994aBeal, 1995). The complex IV lesion resembles other electron transport chain (ETC) defects known to produce Leber's neuropathy and neuropathy-ataxia-retinitis pigmentosa (Singh et al, 1989;Goto et al, 1990;Shoffner et al, 1990;Howell et al, 1991;Ortiz et al, 1993).…”

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confidence: 99%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

242

140

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Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to 0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4,5-triphosphate (InsP 3 )-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP 3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. ␤-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.

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Reduced platelet cytochrome c oxidase activity in Alzheimer's disease

Cited by 197 publications

References 0 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

Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

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