Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

Forero, Diego A.; Casadesús, Gemma; Perry, George; Arboleda, Humberto

doi:10.1111/j.1582-4934.2006.tb00439.x

Cited by 77 publications

(37 citation statements)

References 109 publications

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“…When neuronal DNA damage resulting from oxidative stress is not completely repaired, it can cause accumulated synaptic protein alterations (27, 28). Postsynaptic regions are subjected to particularly high levels of calcium influx and oxidative stress as a result of local activation of glutamate receptors; therefore, they are likely sites at which neurodegenerative processes are initiated in AD (29).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress in the Progression of Alzheimer Disease in the Frontal Cortex

Ansari

Scheff

2010

J Neuropathol Exp Neurol

506

359

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We investigated oxidative stress in human postmortem frontal cortex from individuals characterized as mild-cognitive impairment (n = 8), mild/moderate Alzheimer disease (AD) (n = 4), and late stage AD (n = 9). Samples from subjects with no cognitive impairment (n = 10) that were age- and postmortem interval-matched with these cases were used as controls. The short postmortem interval brain samples were processed for postmitochondrial supernatant (PMS), non-synaptic mitochondria, and synaptosome fractions. Samples were analyzed for several antioxidants (glutathione [GSH], glutathione peroxidase [GPx], glutathione reductase, glutathione-S-transferase [GST] glucose-6-phosphate dehydrogenase, superoxide dismutase [SOD], catalase) and the oxidative marker, thiobarbituric acid reactive substances. The tissue was also analyzed for possible changes in protein damage using neurochemical markers for protein carbonyls, 3-nitrotyrosine, 4-hydroxynonenal, and acrolein. All 3 neuropil fractions (PMS, mitochondrial, and synaptosomal) demonstrated significant disease-dependent increases in oxidative markers. The highest changes were observed in the synaptosomal fraction. Both mitochondrial and synaptosomal fractions had significant declines in antioxidants (GSH, GPx, GST, and SOD). Levels of oxidative markers significantly correlated with Mini-Mental Status Examination scores. Oxidative stress was more localized to the synapses, with levels increasing in a disease-dependent fashion. These correlations implicate an involvement of oxidative stress in AD-related synaptic loss.

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Section: Introductionmentioning

confidence: 99%

Oxidative Stress in the Progression of Alzheimer Disease in the Frontal Cortex

Ansari

Scheff

2010

J Neuropathol Exp Neurol

506

359

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“…Furthermore oxidative stress, a common pathogenic feature of both dementia types [30], induces a down regulation of the occludin expression that leads to BBB breakdown [31]. …”

Section: Introductionmentioning

confidence: 99%

Occludin is overexpressed in Alzheimer's disease and vascular dementia

Romanitan

Popescu

Winblad

et al. 2007

J Cellular Molecular Medi

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The tight junctions (TJs) are key players in the control of blood-brain barrier (BBB) properties, the most complex TJs in the vascular system being found in the endothelial cells of brain capillaries. One of the main TJs proteins is occludin, which anchors plasma membranes of neighbour cells and is present in large amounts in the brain endothelia. Previous studies demonstrated that disruption of BBB in various pathological situations associates with changes in occludin expression, and this change could be responsible for malfunction of BBB. Therefore in this study, applying an immunohistochemical approach, we decided to explore the occludin expression in frontal cortex (FC) and basal ganglia in ageing control, Alzheimer's disease (AD), and vascular dementia (VD) brains, as far as all these pathologies associate microangiopathy and disruption of BBB. Strikingly, we found selected neurons, astrocytes and oligodendrocytes expressing occludin, in all cases studied. To estimate the number of occludin-expressing neurons, we applied a stereological approach with random systematic sampling and the unbiased optical fractionator method. We report here a significant increase in ratio of occludin-expressing neurons in FC and basal ganglia regions in both AD and VD as compared to ageing controls. Within the cerebral cortex, occludin was selectively expressed by pyramidal neurons, which are the ones responsible for cognitive processes and affected by AD pathology. Our findings could be important in unravelling new pathogenic pathways in dementia disorders and new functions of occludin and TJs.

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“…In terms of functional analyses, we found an enrichment of categories such as gene ontologies related to neural transmission and plasticity and signaling networks linked to synaptic plasticity (such as Wnt and Notch), which have been previously postulated as underlying several NPD [27-29]. Of special interest, from a systems biology perspective, we found several topographic parameters of protein-protein interaction networks that were significant for NPD genes [30, 31].…”

Section: Discussionmentioning

confidence: 92%

Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders

Forero

Quiroga

Perry

2016

TONEUJ

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Background:In recent years, a large number of studies around the world have led to the identification of causal genes for hereditary types of common and rare neurological and psychiatric disorders.Objective: To explore the functional and genomic features of known human genes mutated in neuropsychiatric disorders.Methods: A systematic search was used to develop a comprehensive catalog of genes mutated in neuropsychiatric disorders (NPD). Functional enrichment and protein-protein interaction analyses were carried out. A false discovery rate approach was used for correction for multiple testing.Results: We found several functional categories that are enriched among NPD genes, such as gene ontologies, protein domains, tissue expression, signaling pathways and regulation by brain-expressed miRNAs and transcription factors. Sixty six of those NPD genes are known to be druggable. Several topographic parameters of protein-protein interaction networks and the degree of conservation between orthologous genes were identified as significant among NPD genes.Conclusion:These results represent one of the first analyses of enrichment of functional categories of genes known to harbor mutations for NPD. These findings could be useful for a future creation of computational tools for prioritization of novel candidate genes for NPD.

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Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

Cited by 77 publications

References 109 publications

Oxidative Stress in the Progression of Alzheimer Disease in the Frontal Cortex

Oxidative Stress in the Progression of Alzheimer Disease in the Frontal Cortex

Occludin is overexpressed in Alzheimer's disease and vascular dementia

Functional and Genomic Features of Human Genes Mutated in Neuropsychiatric Disorders

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