The Role of NADPH Oxidases and Oxidative Stress in Neurodegenerative Disorders

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(12), P. 3824 - 3824

Published: Nov. 30, 2018

For a number of years, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) was synonymous with NOX2/gp91phox and considered to be peculiarity professional phagocytic cells. Over the last decade, several more homologs have been identified based on current research, NOX family consists NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1 DUOX2 enzymes. NOXs are electron transporting membrane proteins that responsible for reactive oxygen species (ROS) generation—primarily superoxide anion (O2●−), although hydrogen peroxide (H2O2) can also generated. Elevated ROS leads oxidative stress (OS), which has associated myriad inflammatory degenerative pathologies. Interestingly, OS is commonality in pathophysiology neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), amyotrophic lateral sclerosis (ALS) multiple (MS). enzymes expressed neurons, glial cells cerebrovascular endothelial NOX-mediated one main causes damage diseases. In this review, we will discuss recent developments our understanding mechanisms linking activity, diseases, particular focus neurovascular component these conditions. We conclude highlighting challenges future opportunities combat age-related disorders by targeting NOXs.

Language: Английский

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Recent Developments in TSPO PET Imaging as A Biomarker of Neuroinflammation in Neurodegenerative Disorders

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(13), P. 3161 - 3161

Published: June 28, 2019

Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve activation of microglia astrocytes. It a common feature many central nervous system disorders, including range neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory cytokines translocator protein (TSPO) ligand binding was shown early animal studies neurodegeneration. These findings have been translated clinical studies, where increases TSPO positron emission tomography (PET) signal occur disease-relevant areas across broad spectrum diseases. While this supports use PET as biomarker to monitor trials novel therapeutics, utility current radioligands has hampered by lack high affinity prevalent form polymorphic (A147T) compared wild type TSPO. This review details recent developments exploration ligand-sensitivity A147T that yielded ligands with improved utility. In addition developing non-discriminating ligand, final frontier research requires understanding cellular functional interpretation signal. Recent insights resulting from single cell analysis microglial phenotypes are reviewed.

Language: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

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Blood‐based biomarkers for Alzheimer's disease

EMBO Molecular Medicine, Journal Year: 2021, Volume and Issue: 14(1)

Published: Dec. 3, 2021

Language: Английский

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The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(50), P. 32145 - 32154

Published: Nov. 30, 2020

Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer's disease (AD). Interleukin (IL)-1β main inducer inflammation and therefore prime target for therapeutic options. The inactive IL-1β precursor requires processing by nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into mature active form. Studies have shown up-regulated brains patients with AD, genetic inactivation NLRP3 improves behavioral tests synaptic plasticity phenotypes murine model disease. In present study, we analyzed effect pharmacological inhibition using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor safe humans. Six-month-old WT APP/PS1 mice were fed standard mouse chow or OLT1177-enriched mo. Morris water maze test revealed impaired learning memory ability 9-mo-old (P = 0.001), which was completely rescued OLT1177 to 0.008 untreated APP/PS1). Furthermore, our findings mo diet can rescue this AD 0.007 addition, microglia less activated 0.07) number plaques reduced cortex 0.03) following administration. We also observed dose-dependent normalization plasma metabolic markers those mice. This study suggests potential treating inflammasome.

Language: Английский

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Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?

Journal of Clinical Medicine, Journal Year: 2019, Volume and Issue: 8(5), P. 651 - 651

Published: May 10, 2019

Alzheimer's disease (AD) is the most prevalent form of dementia. Despite decades research following several theoretical and clinical lines, all existing treatments for disorder are purely symptomatic. AD has traditionally been focused on neuronal glial dysfunction. Although there a wealth evidence pointing to significant vascular component in disease, this angle relatively poorly explored. In review, we consider various aspects dysfunction AD, which impact brain metabolism homeostasis clearance β-amyloid other toxic metabolites. This may potentially precede onset hallmark pathophysiological cognitive symptoms disease. Pathological changes vessel haemodynamics, angiogenesis, cell function, coverage, blood-brain barrier permeability immune migration be related amyloid toxicity, oxidative stress apolipoprotein E (APOE) genotype. These deficits turn contribute parenchymal deposition, neurotoxicity, activation metabolic multiple types. A vicious feedback cycle ensues, with progressively worsening pathology through course Thus, better appreciation importance open new avenues therapy.

Language: Английский

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Neuroinflammation in Alzheimer’s Disease

Biomedicines, Journal Year: 2021, Volume and Issue: 9(5), P. 524 - 524

Published: May 7, 2021

Alzheimer's disease (AD) is a neurodegenerative associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise increasing age. There are currently no effective modifying treatments for AD, resulting in increasingly large socioeconomic personal costs. Increasing age an increase low-grade chronic inflammation (inflammaging) that may contribute the process AD. Although exact mechanisms remain unclear, aberrant elevation reactive oxygen nitrogen species (RONS) levels from several endogenous exogenous processes brain not only affect cell signaling, but also trigger cellular senescence, inflammation, pyroptosis. Moreover, compromised immune privilege allows infiltration peripheral cells infectious agents play role. Additionally, meta-inflammation as well gut microbiota dysbiosis drive neuroinflammatory process. Considering inflammatory/immune pathways dysregulated parallel cognitive dysfunction elucidating relationship between central nervous system facilitate development safe therapy We discuss some current ideas on inflammaging appear summarize details few immunomodulatory strategies being developed selectively target detrimental aspects neuroinflammation without affecting defense against pathogens tissue damage.

Language: Английский

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APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis

Molecular Neurobiology, Journal Year: 2018, Volume and Issue: 56(4), P. 2450 - 2465

Published: July 21, 2018

Language: Английский

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Prevention of dementia in an ageing world: Evidence and biological rationale

Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 64, P. 101045 - 101045

Published: March 19, 2020

As the population ages, number of people with dementia is expected to increase in coming decades, consequences at societal and individual levels. In this narrative review, we provide a summary scientific evidence concerning prevention, focus on following three strategies: 1) Targeting body protect brain, including prevention treatment cardiovascular morbidity; 2) Compensatory interventions counteract brain ageing, education life-long engagement cognitively socially stimulating activities; 3) Lifespan health promotion, such as physically active lifestyle, smoking cessation, healthy balanced diet. Next, consider biological mechanisms by which these strategies may act taking into account main pathways implicated development progression dementia: neurodegeneration, resilience, vascular damage, neuroinflammation, oxidative stress. Based current evidence, line declining trends incidence high-income countries, conclude that timely multidomain preventive actions are promising reduce epidemic worldwide. There still considerable gap between epidemiological its underlying mechanisms. Filling will be crucial move forward

Language: Английский

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RNA 2′-O-Methylation (Nm) Modification in Human Diseases

Genes, Journal Year: 2019, Volume and Issue: 10(2), P. 117 - 117

Published: Feb. 5, 2019

Nm (2′-O-methylation) is one of the most common modifications in RNA world. It has potential to influence molecules multiple ways, such as structure, stability, and interactions, play a role various cellular processes from epigenetic gene regulation, through translation self versus non-self recognition. Yet, building scientific knowledge on matter been hampered for long time by challenges detecting mapping this modification. Today, with latest advancements area, more sites are discovered RNAs (tRNA, rRNA, mRNA, small non-coding RNA) linked normal or pathological conditions. This review aims synthesize Nm-associated human diseases known date tackle indirect links some other biological defects.

Language: Английский

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