Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders

doi:10.1080/01616412.2016.1251711

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Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders

Journal Article•DOI•

Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders

Md. Torequl Islam¹•Institutions (1)

Federal University of Piauí¹

01 Jan 2017-Neurological Research (Neurol Res)-Vol. 39, Iss: 1, pp 73-82

TL;DR: An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review and the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels.

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Abstract: Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.

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Journal Article•DOI•

Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases

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Bee Ling Tan¹, Mohd Esa Norhaizan¹, Winnie-Pui-Pui Liew¹, Heshu Sulaiman Rahman²•Institutions (2)

Universiti Putra Malaysia¹, University of Sulaymaniyah²

16 Oct 2018-Frontiers in Pharmacology

TL;DR: A better understanding of the role of antioxidants involved in redox modulation of inflammation would provide a useful approach for potential interventions, and subsequently promoting healthy longevity.

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Abstract: Aging is the progressive loss of organ and tissue function over time. Growing older is positively linked to cognitive and biological degeneration such as physical frailty, psychological impairment, and cognitive decline. Oxidative stress is considered as an imbalance between pro- and antioxidant species, which results in molecular and cellular damage. Oxidative stress plays a crucial role in the development of age-related diseases. Emerging research evidence has suggested that antioxidant can control the autoxidation by interrupting the propagation of free radicals or by inhibiting the formation of free radicals and subsequently reduce oxidative stress, improve immune function, and increase healthy longevity. Indeed, oxidation damage is highly dependent on the inherited or acquired defects in enzymes involved in the redox-mediated signaling pathways. Therefore, the role of molecules with antioxidant activity that promote healthy aging and counteract oxidative stress is worth to discuss further. Of particular interest in this article, we highlighted the molecular mechanisms of antioxidants involved in the prevention of age-related diseases. Taken together, a better understanding of the role of antioxidants involved in redox modulation of inflammation would provide a useful approach for potential interventions, and subsequently promoting healthy longevity.

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637 citations

Cites background from "Oxidative stress and mitochondrial ..."

...This theory speculates that aging is a consequence of the failure of several defensive mechanisms to respond to the reactive oxygen species (ROS)induced damage, particularly at the mitochondria (Islam, 2017)....
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Journal Article•DOI•

Involvement of Astrocytes in Alzheimer's Disease from a Neuroinflammatory and Oxidative Stress Perspective.

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Rodrigo E. González-Reyes¹, Mauricio O. Nava-Mesa¹, Karina Vargas-Sánchez, Daniel Ariza-Salamanca¹, Laura Mora-Muñoz¹ - Show less +1 more•Institutions (1)

Del Rosario University¹

19 Dec 2017-Frontiers in Molecular Neuroscience

TL;DR: The Aβ/NF-κB interaction in astrocytes may play a central role in these inflammatory and OS changes present in AD, and therapeutic measures highlighting the importance of astroCytes in AD pathology are discussed.

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Abstract: Alzheimer disease (AD) is a frequent and devastating neurodegenerative disease in humans, but still no curative treatment has been developed. Although many explicative theories have been proposed, precise pathophysiological mechanisms are unknown. Due to the importance of astrocytes in brain homeostasis they have become interesting targets for the study of AD. Changes in astrocyte function have been observed in brains from individuals with AD, as well as in AD in vitro and in vivo animal models. The presence of amyloid beta (Aβ) has been shown to disrupt gliotransmission, neurotransmitter uptake, and alter calcium signaling in astrocytes. Furthermore, astrocytes express apolipoprotein E and are involved in the production, degradation and removal of Aβ. As well, changes in astrocytes that precede other pathological characteristics observed in AD, point to an early contribution of astroglia in this disease. Astrocytes participate in the inflammatory/immune responses of the central nervous system. The presence of Aβ activates different cell receptors and intracellular signaling pathways, mainly the advanced glycation end products receptor/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, responsible for the transcription of pro-inflammatory cytokines and chemokines in astrocytes. The release of these pro-inflammatory agents may induce cellular damage or even stimulate the production of Aβ in astrocytes. Additionally, Aβ induces the appearance of oxidative stress (OS) and production of reactive oxygen species and reactive nitrogen species in astrocytes, affecting among others, intracellular calcium levels, NADPH oxidase (NOX), NF-κB signaling, glutamate uptake (increasing the risk of excitotoxicity) and mitochondrial function. Excessive neuroinflammation and OS are observed in AD, and astrocytes seem to be involved in both. The Aβ/NF-κB interaction in astrocytes may play a central role in these inflammatory and OS changes present in AD. In this paper, we also discuss therapeutic measures highlighting the importance of astrocytes in AD pathology. Several new therapeutic approaches involving phenols (curcumin), phytoestrogens (genistein), neuroesteroids and other natural phytochemicals have been explored in astrocytes, obtaining some promising results regarding cognitive improvements and attenuation of neuroinflammation. Novel strategies comprising astrocytes and aimed to reduce OS in AD have also been proposed. These include estrogen receptor agonists (pelargonidin), Bambusae concretio Salicea, Monascin, and various antioxidatives such as resveratrol, tocotrienol, anthocyanins, and epicatechin, showing beneficial effects in AD models.

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336 citations

Cites background from "Oxidative stress and mitochondrial ..."

...Mitochondrial dysfunction in AD seems to be linked to the increased presence of ROS and RNS (Islam, 2017)....
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...↑MnSOD; ↓Cu/Zn SOD Furuta et al., 1995; Maeda et al., 1997 ROS, reactive oxygen species; RNS, reactive nitrogen species; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; nNOS, neuronal form of nitric oxide synthase; GSH, glutathione, GST, glutathione-S-transferase; GFAP, glial fibrillary acidic protein. primary cortical rat astrocytes, the use of a light-generating nanoparticle attenuated Aβ-induced OS and inflammatory responses, through a reduction in the superoxide anion production and a lowering of IL-1β and iNOS expression (Bungart et al., 2014)....
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...Aβ, amyloid-beta; RAGE, receptor for advanced glycation products; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; RNS, reactive nitrogen species, ROS, reactive oxygen species; LP, lipid peroxidation; TNFα, tumor necrosis factor alpha; IL, interleukin; GSH, glutathione; SOD, superoxide dismutase; EAAT, excitatory amino acid transporter; BACE1, beta-secretase 1; NMDA, N-methyl-D-aspartate receptor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase; Ca++, calcium; ABCC1, ATP-binding cassette subfamily C member 1. several cannabinoid receptor agonists such as WIN, 2-AG, and methanandamide (Gajardo-Gómez et al., 2017)....
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...ROS, as well as RNS, are produced under physiological conditions during the common metabolic pathways....
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...↑ROS; ↑RNS ↓SOD; ↓GSH; ↓Catalase Masilamoni et al., 2005b...
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Journal Article•DOI•

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Jiao Luo¹, Kevin Mills², Saskia le Cessie¹, Raymond Noordam¹, Diana van Heemst¹ - Show less +1 more•Institutions (2)

Leiden University Medical Center¹, UCL Institute of Child Health²

01 Jan 2020-Ageing Research Reviews

TL;DR: It is proposed that oxidized vitamin E metabolites may be used to accurately monitor individual functional antioxidant level, which might serve as promising key solutions for future elucidating the impact of oxidative stress on ageing and age-related diseases.

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264 citations

Cites background from "Oxidative stress and mitochondrial ..."

...Ageing is considered to be the predominant risk factor for NDDs, and accumulative oxidative damages during ageing are the main culprits of neurological deterioration (Islam, 2017; Lin and Beal, 2006)....
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...Several papers have speculated oxidative stress as the key component in the etiology of NNDs (Blesa et al., 2015; Islam, 2017; Jiang Jo ur na l P re -p oo f et al., 2016; Khusnutdinova et al., 2008; Kim et al., 2015; Lin and Beal, 2006; Mariani et al., 2005; Niedzielska et al., 2016; Rego and…...
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...Notably, studies suggested that mitochondrial dysfunction plays a causal role in the pathogenesis of NDDs (Cheignon et al., 2018; Islam, 2017)....
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...However, emerging evidence points to the possible etiological role of oxidative stress, especially ROS-induced mitochondrial dysfunction in NDDs (Cheignon et al., 2018; Islam, 2017; Zhao and Zhao, 2013)....
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Journal Article•DOI•

The role of zinc, copper, manganese and iron in neurodegenerative diseases.

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Leda Mezzaroba¹, Daniela Frizon Alfieri¹, Andréa Name Colado Simão¹, Edna Maria Vissoci Reiche¹•Institutions (1)

Universidade Estadual de Londrina¹

01 Sep 2019-Neurotoxicology

TL;DR: Delineating the specific mechanisms by which metals alter redox homeostasis is essential to understand the pathophysiology of AD, PD, and MS and may provide possible new targets for their prevention and treatment of the patients affected by these NDDs.

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Abstract: Metals are involved in different pathophysiological mechanisms associated with neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The aim of this study was to review the effects of the essential metals zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) on the central nervous system (CNS), as well as the mechanisms involved in their neurotoxicity. Low levels of Zn as well as high levels of Cu, Mn, and Fe participate in the activation of signaling pathways of the inflammatory, oxidative and nitrosative stress (ION however, at high levels, the binding of Zn to β-amyloid may enhance formation of fibrillar β-amyloid aggregation, leading to neurodegeneration. High levels of Cu, Mn and Fe participate in the formation α-synuclein aggregates in intracellular inclusions, called Lewy Body, that result in synaptic dysfunction and interruption of axonal transport. In PD, there is focal accumulation of Fe in the substantia nigra, while in AD a diffuse accumulation of Fe occurs in various regions, such as cortex and hippocampus, with Fe marginally increased in the senile plaques. Zn deficiency induces an imbalance between T helper (Th)1 and Th2 cell functions and a failure of Th17 down-regulation, contributing to the pathogenesis of MS. In MS, elevated levels of Fe occur in certain brain regions, such as thalamus and striatum, which may be due to inflammatory processes disrupting the blood-brain barrier and attracting Fe-rich macrophages. Delineating the specific mechanisms by which metals alter redox homeostasis is essential to understand the pathophysiology of AD, PD, and MS and may provide possible new targets for their prevention and treatment of the patients affected by these NDDs.

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212 citations

Journal Article•DOI•

Resveratrol and Brain Mitochondria: a Review

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Fernanda Rafaela Jardim, Fernando Tonon de Rossi¹, Marielle Xavier Nascimento¹, Renata Gabriele da Silva Barros¹, Paula Agrizzi Borges¹, Isabella Cristina Prescilio¹, Marcos Roberto de Oliveira¹ - Show less +3 more•Institutions (1)

Universidade Federal de Mato Grosso¹

01 Mar 2018-Molecular Neurobiology

TL;DR: The effects of resveratrol on brain mitochondria are discussed, which are of pharmacological interest in the case of neurodegenerative diseases, which involve mitochondrial impairment and increased generation of reactive species, leading to neuroinflammation and cell death.

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Abstract: Resveratrol (3,4',5-trihydroxystilbene; C14H12O3) is a polyphenolic phytoalexin found in grapes, berries, peanuts, and wines. Resveratrol has been viewed as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent. Moreover, it has been reported that resveratrol modulates mitochondrial function, redox biology, and dynamics in both in vitro and in vivo experimental models. Resveratrol also attenuates mitochondrial impairment induced by certain stressors. Resveratrol upregulates, for example, mitochondria-located antioxidant enzymes, decreasing the production of reactive species by these organelles. Resveratrol also triggers mitochondrial biogenesis, ameliorating the mitochondria-related bioenergetics status in mammalian cells. In the present work, we discuss about the effects of resveratrol on brain mitochondria. Brain cells (both neuronal and glial) are susceptible to mitochondrial dysfunction due to their high demand for adenosine triphosphate (ATP). Additionally, brain cells consume oxygen (O2) at very high rates, leading to a proportionally high mitochondrial production of reactive species. Therefore, strategies focusing on the maintenance of mitochondrial function in these cell types are of pharmacological interest in the case of neurodegenerative diseases, which involve mitochondrial impairment and increased generation of reactive species, leading to neuroinflammation and cell death. The mechanism by which resveratrol protects mitochondrial function and dynamics is not completely understood, and further research would be necessary in order to investigate exactly how resveratrol affects mitochondria-related parameters. Furthermore, it is particularly important because resveratrol is able to induce cytotoxicity depending on its dosage.

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163 citations

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References

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Journal Article•DOI•

Reactive Oxygen Species and the Central Nervous System

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Barry Halliwell¹•Institutions (1)

University of California, Davis¹

01 Nov 1992-Journal of Neurochemistry

TL;DR: The nature of antioxidants is discussed, it being suggested that antioxidant enzymes and chelators of transition metal ions may be more generally useful protective agents than chain‐breaking antioxidants.

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Abstract: Radicals are species containing one or more unpaired electrons. The oxygen radical superoxide (O 2 - ) and the non-radical oxidants hydrogen peroxide (H2O2) and hypochlorous acid (HOCl) are produced during normal metabolism and perform several useful functions. Excessive production of O 2 - and H2O2 can result in tissue damage, which often involves generation of highly reactive hydroxy 1 radical (· OH) and other oxidants in the presence of “catalytic” iron or copper ions. A major form of antioxidant defence is the storage and transport of iron or copper ions in forms that will not catalyze formation of reactive radicals. Tissue injury, e. g., by ischaemia or trauma, can cause increased iron availability and accelerate free radical reactions. This may be especially important in the brain, since areas of this organ are rich in iron and cerebrospinal fluid cannot bind released iron ions. Oxidative stress upon nervous tissue can produce damage by several interacting mechanisms, including rises in intracellular free Ca2+ and, possibly, release of excitatory amino acids. Recent suggestions that free radical reactions are involved in the neurotoxicity of aluminium and in damage to the substantia nigra in Parkinson’s disease are reviewed. Finally, the nature of antioxidants is discussed, with a suggestion that antioxidant enzymes and chelators of iron ions may be more generally useful protective agents than chain-breaking antioxidants. Careful precautions must be taken in the design of antioxidants for therapeutic use.

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2,968 citations

"Oxidative stress and mitochondrial ..." refers background in this paper

...2 and H2O2 further leading to oxidative stress.[40] Production of reactive species causes peroxidation of the mitochondrial lipid, cardiolipin, and leads to the release of cytochrome complex (Cyt-c) in the cytosol which is the major cause of apoptosis....
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Journal Article•DOI•

Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

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Patrick L. McGeer¹, S. Itagaki, Barry E. Boyes, Edith G. McGeer•Institutions (1)

University of British Columbia¹

01 Aug 1988-Neurology

TL;DR: The detected large numbers of HLA-DR-positive reactive microglia (macrophages) in the substantia nigra of all cases studied with Parkinson's disease and parkinsonism and suggest a frequent coexistence of DAT- and Parkinson-type pathology in elderly patients.

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Abstract: We detected large numbers of HLA-DR-positive reactive microglia (macrophages), along with Lewy bodies and free melanin, in the substantia nigra of all cases studied with Parkinson's disease (5) and parkinsonism with dementia (PD) (5). We found similar, but less extensive, pathology in the substantia nigra of six of nine cases of dementia of the Alzheimer type (DAT) but in only one of 11 age-matched nonneurologic cases. All dementia cases with a premortem diagnosis of DAT or PD showed large numbers of HLA-DR-positive reactive microglia and significant plaque and tangle counts in the hippocampus, as well as reduced cortical choline acetyltransferase activity. One of 11 nondemented controls showed mild evidence of similar cortical pathology. These data indicate that HLA-DR-positive reactive microglia are a sensitive index of neuropathologic activity. They suggest a frequent coexistence of DAT- and Parkinson-type pathology in elderly patients.

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2,526 citations

"Oxidative stress and mitochondrial ..." refers background in this paper

...Chronic neuroinflammation is responsible for the loss of neurons as well as immune sensitivity.[29] Otherwise, inflammatory reactions further activate microglia and astrocytes to generate large amounts of ROS, which is a major cause of chronic oxidative stress....
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Journal Article•DOI•

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.

[...]

Berislav V. Zlokovic¹•Institutions (1)

University of Southern California¹

01 Dec 2011-Nature Reviews Neuroscience

TL;DR: Mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, are examined, and therapeutic opportunities relating to these neurovascular deficits are highlighted.

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Abstract: The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.

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2,256 citations

"Oxidative stress and mitochondrial ..." refers background in this paper

...[48] However, the peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α)-regulated gene transcription has been found to be defective in patients with HD. Generally, PGC-1α regulates the expression of genes involved in electron transport chain complexes and several other genes that grant protection against the deleterious effects of ROS....
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...The NAD(P)H and electron transport chain after an excessive stimulation leads to an overproduction of ROS....
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...Moreover, an increase in the number of RBCs causes deposition of hemoglobin-derived neurotoxic products including iron, which generates neurotoxic ROS.[34] According to Escudero-Lourdes [55] a consequence...
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...It seems that the decrease in the levels of such substances may cause an increase in Aβ level too.[34]...
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...Moreover, an increase in the number of RBCs causes deposition of hemoglobin-derived neurotoxic products including iron, which generates neurotoxic ROS....
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Journal Article•DOI•

Role of oxygen radicals in DNA damage and cancer incidence

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Marian Valko, Mario Izakovic, Milan Mazúr, Christopher J. Rhodes¹, Joshua Telser² - Show less +1 more•Institutions (2)

University of Reading¹, Roosevelt University²

01 Nov 2004-Molecular and Cellular Biochemistry

TL;DR: The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants.

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Abstract: The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC --> TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.

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1,727 citations

"Oxidative stress and mitochondrial ..." refers background in this paper

...[4] Additionally, in the mitochondrial electron transport chain, during energy transduction, a small number of electrons ‘leak’ to oxygen prematurely forms O·− 2 .[5,6] The enzyme inducible nitric oxide synthase (iNOS) causes synthesis of nitric oxide radical (NO ·) in biological tissues....
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...[12] Superoxide anion (O 2 ) is responsible for a number of pathophysiological conditions,[5,6] while NO · for some important physiological processes....
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Journal Article•DOI•

The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes

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Iryna Benilova¹, Eric Karran¹, Bart De Strooper¹•Institutions (1)

Katholieke Universiteit Leuven¹

01 Mar 2012-Nature Neuroscience

TL;DR: The evidence supporting toxic Aβ oligomers as drivers of neurodegeneration is reviewed and some suggestions that might facilitate progress are made to facilitate progress in this complex field.

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Abstract: The 'toxic Aβ oligomer' hypothesis has attracted considerable attention among Alzheimer's disease researchers as a way of resolving the lack of correlation between deposited amyloid-β (Aβ) in amyloid plaques-in terms of both amount and location-and cognitive impairment or neurodegeneration. However, the lack of a common, agreed-upon experimental description of the toxic Aβ oligomer makes interpretation and direct comparison of data between different research groups impossible. Here we critically review the evidence supporting toxic Aβ oligomers as drivers of neurodegeneration and make some suggestions that might facilitate progress in this complex field.

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1,722 citations

"Oxidative stress and mitochondrial ..." refers background in this paper

...dysfunction lead to cell death and dementia.[30,31] The transition metals, Cu2+, Zn2+, and Fe3+, have been found to be involved in Aβ aggregation and oxidative damage in AD patients....
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