Autopsy Samples of Alzheimer's Cortex Show Increased Peroxidation In Vitro

Subbarao, Kala V.; Richardson, Jeremy; Ang, Lee Cyn

doi:10.1111/j.1471-4159.1990.tb08858.x

Cited by 415 publications

(187 citation statements)

References 24 publications

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“…Our results therefore suggest that increase in lipid peroxides is likely to result from attack on polyunsaturated fatty acids in cell-membrane phospholipids by free radicals. These findings on peripheral cells are in agreement with several studies that provide evidence for excess lipoperoxidation and protein oxidation associated with A␤ deposits in APP and PS-1 AD brain and mutant mice [9,12,45,51,62]. It has been shown that 4-HNE, generated in response to A␤-oxidative insults, can directly induce neuronal apoptosis at pathophysiological concentrations [41].…”

Section: Discussionsupporting

confidence: 91%

“…Several reports provide strong evidence for amyloid lipid peroxidation within the AD brain [10,30,45,48,62,68]. A␤ can fragment and generate free radical peptides which have potent lipoperoxidising effects on the synaptosomal membranes in the neocortex [12,17,32].…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondria are the major subcellular source of superoxide anion radical, which can interact with nitric oxide (NO) to form peroxynitrite [12,71]. ROS and peroxynitrite accumulation results in damage to major macromolecules in cells, including lipids, proteins and nucleic acids [47,60,62,68]. The lipoperoxidation process could influence the pathogenesis of AD [55,59].…”

Section: Introductionmentioning

confidence: 99%

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Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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Much experimental evidence suggests that an imbalance in cellular redox status is a major factor in the pathogenesis of Alzheimer's disease (AD). Our previous data showed a marked increase in membrane lipoperoxidation in primary fibroblasts from familial AD (FAD) patients. In the present study, we demonstrate that when oligomeric structures of A␤ 1-40 and A␤ 1-42 are added to the culture media, they accumulate quicker near the plasma membrane, and are internalized faster and mostly in APPV717I fibroblasts than in age-matched healthy cells; this results in an earlier and sharper increase in the production of reactive oxygen species (ROS). Higher ROS production leads in turn to an increase in membrane oxidative-injury and significant impairment of cellular antioxidant capacity, giving rise to apoptotic cascade activation and finally to a necrotic outcome. In contrast, healthy fibroblasts appear more resistant to amyloid oxidative-attack, possibly as a result of their plasma membrane integrity and powerful antioxidant capacity. Our data are consistent with increasing evidence that prefibrillar aggregates, compared to mature fibrils, are likely the more toxic species of the peptides. These findings provide compelling evidence that cells bearing increased membrane lipoperoxidation are more susceptible to aggregate toxicity as a result of their reduced ability to counteract amyloid oligomeric attack.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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“…49 Interestingly, the work conducted by Arivazhagan and Panneerselvam 46 found that intraperitoneal administration of the antioxidant DL-a-lipoic acid to aged mice returned the levels of serotonin to similar levels found in young mice. In addition, the administration of selective serotonin reuptake inhibitors has been shown to increase cognitive performance in nondemented individuals although these findings have been challenged.…”

Section: Discussionmentioning

confidence: 98%

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

et al. 2005

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Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P ¼ 0.002, AH2 P ¼ 0.014), the test of semantic memory (P ¼ 0.010) and general cognitive ability (P ¼ 0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly. Keywords: serotonin transporter; polymorphism; cognition; memory; genes; associationIn an increasingly long-lived population severe cognitive impairment, caused by either the normal ageing process or dementia, is an escalating problem that currently has no effective treatment. Cognitive ability and its rate of decline are highly heritable and both have been shown to predict dementia onset. [1][2][3][4] Of the 13 quantitative trait loci (QTL) currently associated with the level of cognitive ability in normal individuals the most widely reported are located in genes involved in synaptic transmission. 5 These comprise the adrenergic receptor 2A, catechol-O-methyltransferase, dopamine receptor D2, cholinergic muscarinic 2 receptor, brain-derived neurotrophic factor, metabotrophic glutamate receptor 3 and the serotonin receptor 2A. [6][7][8][9][10][11][12][13] To date only the apolipoprotein E e4 allele has been associated with cognitive decline in nondemented individuals and this finding has been challenged. [14][15][16][17][18][19] Serotonin has been shown to play a role in brain development and cognitive functioning. 20,21 There is also a decrease in total brain serotonin with age that may predispose the elderly to depression, dementia and cognitive dysfunction. 22 Despite the importance of serotonin as a modulator of memory and learning the influence of two functional polymorphisms (HTTLPR and VNTR2) in the SLC6A4 gene, which codes for a protein responsible for the reuptake of serotonin, have n...

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“…Because of its high rate of oxygen consumption and high content of polyunsaturated fatty acids, the brain is easily susceptible to increased oxidative stress. Increased protein, lipid and DNA oxidation has been demonstrated in brain samples of AD patients [6]. Protein carbonyl 3, 3'-dityrosine and 3-nitrotyrosine levels in post-mortem brain samples of AD patients exhibit increased oxidative and nitrosative protein modification in the hippocampal and neocortical regions [7].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

Srinivasan¹

2012

J Neurol Res

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Alzheimer's disease (AD) is characterized by a progressive loss of memory and cognitive function, and by behavioural and sleep disturbances, including insomnia. The pathophysiology of AD has been attributed to oxidative stress-induced amyloid-β protein (Aβ) deposition. Abnormal tau protein, mitochondrial dysfunction and protein hyper-phosphorylation have been demonstrated in neural tissues of AD patients. AD patients exhibit severe sleep-wake disturbances and these sleep disturbances are associated with rapid cognitive decline and memory impairment. Optimally effective management of AD patients will likely require a drug that can arrest Aβ -induced neurotoxic effects and can also restore the disturbed sleep-wake rhythm, with improvement in sleep quality. In this context, the pineal hormone melatonin has been demonstrated to be an effective antioxidant that can prevent Aβ -induced neurotoxic effects through a variety of mechanisms. Sleep deprivation itself produces many effects including oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, altered proteosomal processing and abnormal activation of enzymes. In addition to treating the signs and symptoms of AD, treatment of sleep disturbances may also be necessary for preventing and arresting AD progression. Besides melatonin, a number of melatonergic agonists such as ramelteon, agomelatine and tasimelteon are now used clinically for treating insomnia and other sleep disorders. Their use may also be beneficial in treating Alzheimer's disease.

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Autopsy Samples of Alzheimer's Cortex Show Increased Peroxidation In Vitro

Cited by 415 publications

References 24 publications

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

Alzheimer’s Disease: Focus on the Neuroprotective Role of Melatonin

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