Oxidative Alterations in Alzheimer's Disease

Markesbery, William R.; Carney, John M.

doi:10.1111/j.1750-3639.1999.tb00215.x

Cited by 720 publications

(385 citation statements)

References 124 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: 88%

“…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: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

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“…90 Although in TBI-related studies, 4-HNE levels were evaluated in brain tissue, studies examining this compound in CSF and plasma have been carried out for other neurologic disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and stroke. [91][92][93] …”

Section: -Hydroxynonenalmentioning

confidence: 99%

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

et al. 2010

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confidence: 99%

“…Free radical reactions and oxidative stress [28,29], as well as unregulated immune response [30,31], are believed to be key factors for the pathogenesis of AD, whereas recent reports suggested a link between heart disease, hypercholesterolemia, and AD [32,33]. Thus, the well-documented antioxidant, anti-inflammatory, and antiatherogenic properties of OE may offer a multistage approach against the diverse mechanisms, which are inherent to AD.…”

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confidence: 99%

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

Bazoti

Bergquist

Markides

et al. 2008

J. Am. Soc. Mass Spectrom.

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Abnormal accumulation and aggregation of amyloid-␤-peptide (A␤) eventually lead to the formation and cerebral deposition of amyloid plaques, the major pathological hallmark in Alzheimer's disease (AD). Oleuropein (OE), an Olea europaea L. derived polyphenol, exhibits a broad range of pharmacological properties, such as antioxidant, anti-inflammatory, and antiatherogenic, which could serve as combative mechanisms against several reported pathways involved in the pathophysiology of AD. The reported noncovalent interaction between A␤ and OE could imply a potential antiamyloidogenic role of the latter on the former via stabilization of its structure and prevention of the adaptation of a toxic ␤-sheet conformation. The established ␤-sheet conformation of the A␤ hydrophobic carboxy-terminal region and the dependence of its toxicity and aggregational propensity on its secondary structure make the determination of the binding site between A␤ and OE highly important for assessing the role of the interaction. In this study, two different proteolytic digestion protocols, in conjunction with high-sensitivity electrospray ionization mass spectrometric analysis of the resulting peptide fragments, were used to determine the noncovalent binding site of OE on A␤ and revealed the critical regions for the interaction. and its aggregational properties depend on both the peptide concentration and conformation, as well as on the solution conditions and pH [2,3]. It has been reported that reduction of the A␤ production, by controlling the cleavage of the larger transmembrane amyloid precursor protein (APP), or inhibition of its aggregation by using small molecules, which may interact noncovalently with A␤ and stabilize its structure, could serve as preventive or therapeutic approaches against AD [4]. In general, interruption of noncovalent interactions between protein and peptides, or even more between proteins/peptides and ligands can cause abnormalities, which often lead to diseases [5]. One interaction of this kind has been established between the Olea europaea derived bioactive compound, oleuropein (OE), and A␤ by means of electrospray ionization mass spectrometry (ESI-MS) [6]. This interaction could prove potent in inhibiting its aggregation.OE is a polyphenol extracted from the fruits and leaves of Olea europaea L. and possesses a wide range of pharmacological properties, such as antioxidant [7][8][9], anti-inflammatory [10, 11], antiatherogenic [12-14], antibacterial [15][16][17], and anticancer [18,19]. Moreover, OE and its metabolites have been shown to be potent against contemporary diseases, such as HIV [20,21] and osteoporosis [22,23]. Interestingly, in vitro [24] and epidemiological [25] studies demonstrated the positive impact of polyphenols on the onset of age-related disorders, such as dementia [26,27].It is regarded that the pathophysiology of AD is tangled and many theories have been proposed to illumine its mechanism. Free radical reactions and oxidative stress [28,29], as well as unregulated immune response [30,3...

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Oxidative Alterations in Alzheimer's Disease

Cited by 720 publications

References 124 publications

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry

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