Lymphocyte Oxidative DNA Damage and Plasma Antioxidants in Alzheimer Disease

Mecocci, Patrizia; Polidori, Maria Cristina; Cherubini, Antonio; Ingegni, Tiziana; Mattioli, Paola; Catani, Marco; Rinaldi, Patrizia; Cecchetti, Roberta; Stahl, Wilhelm; Senin, Umberto; Beal, M. Flint

doi:10.1001/archneur.59.5.794

Cited by 205 publications

(137 citation statements)

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“…Lower plasma antioxidant levels and alterations in antioxidant enzyme activities are reported in mild cognitive impairment (MCI) patients and patients at early AD stages [19,[36][37][38][39] suggesting a systemic imbalance between ROS production and antioxidant defense systems in the plasma of AD patients and this is substantiated by increases in DNA, lipid, and protein oxidation products found in blood and cerebrospinal fluid (CSF) obtained from AD patients in comparison with controls [35,40,41]. Reflecting such a systemic oxidative imbalance in AD, we also found oxidative damage in olfactory neurons and the surrounding epithelial cells from AD donors [42], and another group reported increased 8-hydroxy-deoxyguanosine (8OHdG) in the DNA of lymphocytes from AD donors [43], which inversely correlated with the plasma levels of several antioxidant carotenoids [44].…”

Section: Vascular Oxidative Stress In Alzheimer Diseasesupporting

confidence: 58%

Vascular oxidative stress in Alzheimer disease

Zhu

Smith

Honda

et al. 2007

Journal of the Neurological Sciences

160

156

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Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process. KeywordsAlzheimer disease; hypoperfusion; mitochondria; nitric oxide; nitric oxide synthase; oxidative stress; vascular abnormalitiesCorrespondence to: George Perry, Ph.D., College of Sciences, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, Texas 78249-0661 USA, , george.perry@utsa.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . Therefore, perivascular Aβ deposits may be a risk factor for reduced regional CBF [7]. Ultrastructural studies on blood vessels associated with Aβ deposits have shown their intermittent association with membrane abnormalities of smooth muscle cells [5]. Indeed, in AD cases with a clinical history of cerebral bleeding, the muscle layer is sometimes completely replaced by Aβ deposits, suggesting that the vascular system may be an initiator for the development of diseas...

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Section: Vascular Oxidative Stress In Alzheimer Diseasesupporting

confidence: 58%

Vascular oxidative stress in Alzheimer disease

Zhu

Smith

Honda

et al. 2007

Journal of the Neurological Sciences

160

156

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“…An increased DNA oxidative damage in peripheral leukocytes, previously reported in AD subjects [81,82], has been recently found in MCI [85], as well as in nuclear and mitochondrial DNA isolated from frontal, parietal and temporal brain lobes [127].…”

Section: Biomarkersmentioning

confidence: 59%

Mild Cognitive Impairment: A Systematic Review

Mariani

Monastero

Mecocci

2007

JAD

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213

182

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Abstract. MCI is a nosological entity proposed as an intermediate state between normal aging and dementia. The syndrome can be divided into two broad subtypes: amnestic MCI (aMCI) characterized by reduced memory, and non-amnestic MCI (naMCI) in which other cognitive functions rather than memory are mostly impaired. aMCI seems to represent an early stage of AD, while the outcomes of the naMCI subtypes appear more heterogeneous -including vascular dementia, frontotemporal dementia or dementia with Lewy bodies-but this aspect is still under debate. MCI in fact represents a condition with multiple sources of heterogeneity, including clinical presentation, etiology, and prognosis. To improve classification and prognosis, there is a need for more sensitive instruments specifically developed for MCI as well as for more reliable methods to determine its progression or improvement. Current clinical criteria for MCI should be updated to include restriction in complex ADL; also the diagnostic and prognostic role of behavioral symptoms and motor dysfunctions should be better defined. A multidisciplinary diagnostic approach including biological and neuroimaging techniques may probably represent the best option to predict the conversion from MCI to dementia. In this review we discuss the most recent aspects related to the epidemiological, clinical, neuropathological, neuroimaging, biochemical and therapeutic aspects of MCI, with specific attention to possible markers of conversion to dementia.

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“…Oxidative stress represents the loss of balance between the processes of the creation of free radicals and those that are responsible for the removal of oxidized macromolecules (antioxidative cascade) which again leads to cellular dysfunction (changes in cellular homeostasis) and results in increased genomic instability and eventually in cell death (25). Most likely, the oxidative stress is the essence of a greater DNA damage compared to adequate control (18,26,27) as one of the initial factors that lead to further genomic instability (28)(29)(30). There is substantial evidence supporting the fact that genetic instability is increased in AD lymphocytes compared to corresponding controls.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of DNA Damage in the Lymphocytes of Young, Elderly and Alzheimer’s Disease Patients Treated with β-Estradiol in the Comet Assay

Žrsković¹,

Djelić²,

Bajićs³

et al. 2013

Journal of Medical Biochemistry

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Summary Background: The antioxidant activity of estrogen has a be ne - ficial impact in Alzheimer’s disease. A variety of clinical stu - dies have demonstrated that estrogen replacement therapy in postmenopausal women results in a lower frequency of AD, delaying the onset of the neurodegenerative cascade. On the other hand, it has been demonstrated that estrogens may exhibit genotoxic effects, especially at elevated tissue concentrations. Therefore, the aim of this study was to determine whether b-estradiol induces DNA damage in the peripheral blood lymphocytes of healthy young females and males, healthy elderly females and males and females and males with Alzheimer’s disease. Methods: All experiments were performed using the alkaline version of the Comet assay (single cell gel electrophoresis), on six donors per each experimental group and controls. Results: In the Comet assay, a significant increase of DNA migration was observed in the lymphocytes of all treated groups (young and elderly females, young and elderly males, AD females and AD males) at all b-estradiol concentrations (50 mmol/L, 100 mmol/L and 250 mmol/L) used in this investigation. In all the experiments cell viability was over 80%. Conclusions: Lymphocytes are sensitive to the test concentrations of b-estradiol in the Comet assay regardless of gender, age and health condition of the examined subjects. Therefore, the role of b-estradiol in cellular DNA damage has been confirmed.

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Lymphocyte Oxidative DNA Damage and Plasma Antioxidants in Alzheimer Disease

Abstract: Markers of oxidative damage are increased in AD and correlate with decreased levels of plasma antioxidants. These findings suggest that lymphocyte DNA 8-OHdG content in patients with AD reflects a condition of increased oxidative stress related to a poor antioxidant status.

Cited by 205 publications

References 56 publications

Vascular oxidative stress in Alzheimer disease

Vascular oxidative stress in Alzheimer disease

Mild Cognitive Impairment: A Systematic Review

Evaluation of DNA Damage in the Lymphocytes of Young, Elderly and Alzheimer’s Disease Patients Treated with β-Estradiol in the Comet Assay

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