Increased Peroxidation and Reduced Antioxidant Enzyme Activity in Alzheimer's Disease

Marcus, David L.; Thomas, Christopher; Rodriguez, Charles F.; Simberkoff, Katherine; Tsai, Jir S.; Strafaci, James A.; Freedman, Michael L.

doi:10.1006/exnr.1997.6750

Cited by 456 publications

(250 citation statements)

References 25 publications

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“…The healthy brain is protected from oxidative injury by antioxidant defences that include antioxidant enzymes and free radical scavengers. Many recent investigations have strengthened the hypothesis that an impairment in cellular total antioxidant capacity (TAC) plays a central role in AD [47,46]. Recently, we have found that lymphoblasts and fibroblasts carrying APP and PS-1 gene mutations have a significant TAC impairment compared to healthy controls [15].…”

Section: Introductionmentioning

confidence: 89%

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: Introductionmentioning

confidence: 89%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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“…Studies have shown that the expression of target genes of Nrf2 were increased in AD patients. It has been demonstrated that the expression levels of HO-1, GCLM and p62 are increased in the temporal cortices of AD patients compared with that of controls (Marcus et al 1998). In the normal hippocampus, Nrf2 is expressed in neurons and predominantly localised in the nucleus.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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“…In disease, various modifications of macromolecules such as sugars, lipids, proteins, and nucleic acids, come into play, and it is now well established that neurodegenerative diseases are associated with oxidative imbalance and its sequelae. In the case of AD, many lines of evidence now indicate that ROS induced by redoxactive metals including iron play a pivotal role in pathogenesis [20][21][22][23][24][25][26][27][28][29]. In the following sections, we will discuss the suggested mechanisms of iron in the neuropathology of AD.…”

Section: Introductionmentioning

confidence: 99%

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

et al. 2007

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Although iron is essential in maintaining the function of the central nervous system, it is a potent source of reactive oxygen species. Excessive iron accumulation occurs in many neurodegenerative diseases including Alzheimer disease (AD), Parkinson's disease, and Creutzfeldt-Jakob disease, raising the possibility that oxidative stress is intimately involved in the neurodegenerative process. AD in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

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Increased Peroxidation and Reduced Antioxidant Enzyme Activity in Alzheimer's Disease

Cited by 456 publications

References 25 publications

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

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