Antioxidants

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16 pages, 2015 KiB

Open AccessArticle

Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics

by Liu-Yun Wu, Cheuk Ni Kan, Irwin K. Cheah, Joyce Ruifen Chong, Xin Xu, Henri Vrooman, Saima Hilal, Narayanaswamy Venketasubramanian, Christopher P. Chen, Barry Halliwell and Mitchell K.P. Lai

Antioxidants 2022, 11(9), 1717; https://doi.org/10.3390/antiox11091717 - 30 Aug 2022

Cited by 16 | Viewed by 4193

Abstract

Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between [...] Read more.

Low blood concentrations of the diet-derived compound ergothioneine (ET) have been associated with cognitive impairment and cerebrovascular disease (CeVD) in cross-sectional studies, but it is unclear whether ET levels can predict subsequent cognitive and functional decline. Here, we examined the temporal relationships between plasma ET status and cognition in a cohort of 470 elderly subjects attending memory clinics in Singapore. All participants underwent baseline plasma ET measurements as well as neuroimaging for CeVD and brain atrophy. Neuropsychological tests of cognition and function were assessed at baseline and follow-up visits for up to five years. Lower plasma ET levels were associated with poorer baseline cognitive performance and faster rates of decline in function as well as in multiple cognitive domains including memory, executive function, attention, visuomotor speed, and language. In subgroup analyses, the longitudinal associations were found only in non-demented individuals. Mediation analyses showed that the effects of ET on cognition seemed to be largely explainable by severity of concomitant CeVD, specifically white matter hyperintensities, and brain atrophy. Our findings support further assessment of plasma ET as a prognostic biomarker for accelerated cognitive and functional decline in pre-dementia and suggest possible therapeutic and preventative measures. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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19 pages, 2262 KiB

Open AccessArticle

Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction

by Kerry C. Ryan, Jocelyn T. Laboy and Kenneth R. Norman

Antioxidants 2022, 11(9), 1642; https://doi.org/10.3390/antiox11091642 - 24 Aug 2022

Cited by 4 | Viewed by 1826

Abstract

Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations [...] Read more.

Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue SEL-12 results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1/Nrf. Our study reveals that SEL-12/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1/Nrf antioxidant activity. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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Review

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23 pages, 2674 KiB

Open AccessReview

Roles of Oxidative Stress in Synaptic Dysfunction and Neuronal Cell Death in Alzheimer’s Disease

by Germán Plascencia-Villa and George Perry

Antioxidants 2023, 12(8), 1628; https://doi.org/10.3390/antiox12081628 - 17 Aug 2023

Cited by 11 | Viewed by 2809

Abstract

Alzheimer’s disease (AD) is a brain disorder that progressively undermines memory and thinking skills by affecting the hippocampus and entorhinal cortex. The main histopathological hallmarks of AD are the presence of abnormal protein aggregates (Aβ and tau), synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, [...] Read more.

Alzheimer’s disease (AD) is a brain disorder that progressively undermines memory and thinking skills by affecting the hippocampus and entorhinal cortex. The main histopathological hallmarks of AD are the presence of abnormal protein aggregates (Aβ and tau), synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. However, oxidative stress or oxidative damage is also evident and commonly overlooked or considered a consequence of the advancement of dementia symptoms. The control or onset of oxidative stress is linked to the activity of the amyloid-β peptide, which may serve as both antioxidant and pro-oxidant molecules. Furthermore, oxidative stress is correlated with oxidative damage to proteins, nucleic acids, and lipids in vulnerable cell populations, which ultimately lead to neuronal death through different molecular mechanisms. By recognizing oxidative stress as an integral feature of AD, alternative therapeutic or preventive interventions are developed and tested as potential or complementary therapies for this devastating neurodegenerative disease. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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27 pages, 4088 KiB

Open AccessReview

Alzheimer’s Disease and Green Tea: Epigallocatechin-3-Gallate as a Modulator of Inflammation and Oxidative Stress

by Víctor Valverde-Salazar, Daniel Ruiz-Gabarre and Vega García-Escudero

Antioxidants 2023, 12(7), 1460; https://doi.org/10.3390/antiox12071460 - 20 Jul 2023

Cited by 7 | Viewed by 3051

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, characterised by a marked decline of both memory and cognition, along with pathophysiological hallmarks including amyloid beta peptide (Aβ) accumulation, tau protein hyperphosphorylation, neuronal loss and inflammation in the brain. Additionally, oxidative stress [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia, characterised by a marked decline of both memory and cognition, along with pathophysiological hallmarks including amyloid beta peptide (Aβ) accumulation, tau protein hyperphosphorylation, neuronal loss and inflammation in the brain. Additionally, oxidative stress caused by an imbalance between free radicals and antioxidants is considered one of the main risk factors for AD, since it can result in protein, lipid and nucleic acid damage and exacerbate Aβ and tau pathology. To date, there is a lack of successful pharmacological approaches to cure or even ameliorate the terrible impact of this disease. Due to this, dietary compounds with antioxidative and anti-inflammatory properties acquire special relevance as potential therapeutic agents. In this context, green tea, and its main bioactive compound, epigallocatechin-3-gallate (EGCG), have been targeted as a plausible option for the modulation of AD. Specifically, EGCG acts as an antioxidant by regulating inflammatory processes involved in neurodegeneration such as ferroptosis and microglia-induced cytotoxicity and by inducing signalling pathways related to neuronal survival. Furthermore, it reduces tau hyperphosphorylation and aggregation and promotes the non-amyloidogenic route of APP processing, thus preventing the formation of Aβ and its subsequent accumulation. Taken together, these results suggest that EGCG may be a suitable candidate in the search for potential therapeutic compounds for neurodegenerative disorders involving inflammation and oxidative stress, including Alzheimer’s disease. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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16 pages, 624 KiB

Open AccessReview

Oxidative Stress in Brain in Amnestic Mild Cognitive Impairment

by D. Allan Butterfield

Antioxidants 2023, 12(2), 462; https://doi.org/10.3390/antiox12020462 - 11 Feb 2023

Cited by 5 | Viewed by 1700

Abstract

Amnestic mild cognitive impairment (MCI), arguably the earliest clinical stage of Alzheimer disease (AD), is characterized by normal activities of daily living but with memory issues but no dementia. Oxidative stress, with consequent damaged key proteins and lipids, are prominent even in this [...] Read more.

Amnestic mild cognitive impairment (MCI), arguably the earliest clinical stage of Alzheimer disease (AD), is characterized by normal activities of daily living but with memory issues but no dementia. Oxidative stress, with consequent damaged key proteins and lipids, are prominent even in this early state of AD. This review article outlines oxidative stress in MCI and how this can account for neuronal loss and potential therapeutic strategies to slow progression to AD. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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14 pages, 1152 KiB

Open AccessReview

Ether Lipid-Mediated Antioxidant Defense in Alzheimer’s Disease

by Mariona Jové, Natàlia Mota-Martorell, Èlia Obis, Joaquim Sol, Meritxell Martín-Garí, Isidre Ferrer, Manuel Portero-Otin and Reinald Pamplona

Antioxidants 2023, 12(2), 293; https://doi.org/10.3390/antiox12020293 - 28 Jan 2023

Cited by 7 | Viewed by 2067

Abstract

One of the richest tissues in lipid content and diversity of the human body is the brain. The human brain is constitutively highly vulnerable to oxidative stress. This oxidative stress is a determinant in brain aging, as well as in the onset and [...] Read more.

One of the richest tissues in lipid content and diversity of the human body is the brain. The human brain is constitutively highly vulnerable to oxidative stress. This oxidative stress is a determinant in brain aging, as well as in the onset and progression of sporadic (late-onset) Alzheimer’s disease (sAD). Glycerophospholipids are the main lipid category widely distributed in neural cell membranes, with a very significant presence for the ether lipid subclass. Ether lipids have played a key role in the evolution of the human brain compositional specificity and functionality. Ether lipids determine the neural membrane structural and functional properties, membrane trafficking, cell signaling and antioxidant defense mechanisms. Here, we explore the idea that ether lipids actively participate in the pathogenesis of sAD. Firstly, we evaluate the quantitative relevance of ether lipids in the human brain composition, as well as their role in the human brain evolution. Then, we analyze the implications of ether lipids in neural cell physiology, highlighting their inherent antioxidant properties. Finally, we discuss changes in ether lipid content associated with sAD and their physiopathological implications, and propose a mechanism that, as a vicious cycle, explains the potential significance of ether lipids in sAD. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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55 pages, 1301 KiB

Open AccessReview

Non-Enzymatic Antioxidants against Alzheimer’s Disease: Prevention, Diagnosis and Therapy

by Angelica Varesi, Lucrezia Irene Maria Campagnoli, Adelaide Carrara, Ilaria Pola, Elena Floris, Giovanni Ricevuti, Salvatore Chirumbolo and Alessia Pascale

Antioxidants 2023, 12(1), 180; https://doi.org/10.3390/antiox12010180 - 12 Jan 2023

Cited by 9 | Viewed by 4389

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although substantial research has been conducted to elucidate the complex pathophysiology of AD, the therapeutic approach still has limited efficacy in clinical practice. Oxidative stress (OS) has been [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although substantial research has been conducted to elucidate the complex pathophysiology of AD, the therapeutic approach still has limited efficacy in clinical practice. Oxidative stress (OS) has been established as an early driver of several age-related diseases, including neurodegeneration. In AD, increased levels of reactive oxygen species mediate neuronal lipid, protein, and nucleic acid peroxidation, mitochondrial dysfunction, synaptic damage, and inflammation. Thus, the identification of novel antioxidant molecules capable of detecting, preventing, and counteracting AD onset and progression is of the utmost importance. However, although several studies have been published, comprehensive and up-to-date overviews of the principal anti-AD agents harboring antioxidant properties remain scarce. In this narrative review, we summarize the role of vitamins, minerals, flavonoids, non-flavonoids, mitochondria-targeting molecules, organosulfur compounds, and carotenoids as non-enzymatic antioxidants with AD diagnostic, preventative, and therapeutic potential, thereby offering insights into the relationship between OS and neurodegeneration. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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26 pages, 2691 KiB

Open AccessReview

Therapeutics of Alzheimer’s Disease: Recent Developments

by Scott Burns, Ashley Selman, Ujala Sehar, Priyanka Rawat, Arubala P. Reddy and P. Hemachandra Reddy

Antioxidants 2022, 11(12), 2402; https://doi.org/10.3390/antiox11122402 - 3 Dec 2022

Cited by 8 | Viewed by 3858

Abstract

With increasing aging, dementia is a growing public health concern globally. Patients with dementia have multiple psychological and behavioral changes, including depression, anxiety, inappropriate behavior, paranoia, agitation, and hallucinations. The major types of dementia are Alzheimer’s disease (AD), vascular dementia (VCID), Lewy body [...] Read more.

With increasing aging, dementia is a growing public health concern globally. Patients with dementia have multiple psychological and behavioral changes, including depression, anxiety, inappropriate behavior, paranoia, agitation, and hallucinations. The major types of dementia are Alzheimer’s disease (AD), vascular dementia (VCID), Lewy body dementia (LBD), frontotemporal dementia (FTD), and mixed dementia (MiAD). Among these, AD is the most common form of dementia in the elderly population. In the last three decades, tremendous progress has been made in understanding AD’s biology and disease progression, particularly its molecular basis, biomarker development, and drug discovery. Multiple cellular changes have been implicated in the progression of AD, including amyloid beta, phosphorylated tau, synaptic damage, mitochondrial dysfunction, deregulated microRNAs, inflammatory changes, hormonal deregulation, and others; based on these changes, therapeutic strategies have been developed, which are currently being tested in animal models and human clinical trials. The purpose of our article is to highlight recent therapeutic strategies’ developments, critically discuss current strategies’ failures, and propose new strategies to combat this devasting mental illness. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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32 pages, 1550 KiB

Open AccessReview

The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives

by Maria Carolina Jurcău, Felicia Liana Andronie-Cioara, Anamaria Jurcău, Florin Marcu, Delia Mirela Ţiț, Nicoleta Pașcalău and Delia Carmen Nistor-Cseppentö

Antioxidants 2022, 11(11), 2167; https://doi.org/10.3390/antiox11112167 - 31 Oct 2022

Cited by 19 | Viewed by 4444

Abstract

Alzheimer’s disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid [...] Read more.

Alzheimer’s disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid plaque formation, increasing amyloid beta clearance, or inhibiting neurofibrillary tangle pathology yielded inconclusive results or failed. Meanwhile, research has identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, and has pointed to novel therapeutic targets such as improving mitochondrial bioenergetics and quality control, diminishing oxidative stress, or modulating the neuroinflammatory pathways. Many novel molecules tested in vitro or in animal models have proven efficient, but their translation into clinic needs further research regarding appropriate doses, delivery routes, and possible side effects. Cell-based therapies and extracellular vesicle-mediated delivery of messenger RNAs and microRNAs seem also promising strategies allowing to target specific signaling pathways, but need further research regarding the most appropriate harvesting and culture methods as well as control of the possible tumorigenic side effects. The rapidly developing area of nanotechnology could improve drug delivery and also be used in early diagnosis. Full article

(This article belongs to the Special Issue Oxidative Stress in Alzheimer's Disease)

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