ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

Antioxidants, Год журнала: 2020, Номер 9(8), С. 743 - 743

Опубликована: Авг. 13, 2020

Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation neuronal damage result in the activation disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation reactive oxygen species (ROS) generation. However, mechanisms linking OS have not been well-defined; thus targeting these cells for clinical benefit has possible. In microglia, ROS generated primarily by NADPH oxidase 2 (NOX2) NOX2 is associated DAMP signalling, amyloid plaque deposition, especially cerebrovasculature. Additionally, originating from both NOX mitochondria may act second messengers propagate immune activation; intracellular signalling underlie excessive OS. Targeting key kinases inflammatory response could cease promote tissue repair. Expression antioxidant proteins dehydrogenase 1 (NQO1), promoted transcription factor Nrf2, which functions control limit Lipid droplet accumulating (LDAM) also represent double-edged sword neurodegenerative sequestering peroxidised lipids non-pathological ageing but becoming dysregulated pro-inflammatory disease. We suggest that future studies should focus on targeted manipulation understand driving inflammatory-related activation. Finally, we discuss recent evidence therapeutic target identification be unbiased founded relevant pathophysiological assays discovery translatable anti-inflammatory therapeutics.

Язык: Английский

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The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer’s Disease—a Critical Review

Molecular Neurobiology, Год журнала: 2018, Номер 56(3), С. 1841 - 1851

Опубликована: Июнь 23, 2018

One of the most important scientific discoveries recent years was disclosure that intestinal microflora takes part in bidirectional communication between gut and brain. Scientists suggest human may even act as "second brain" be responsible for neurodegenerative disorders like Alzheimer's disease (AD). Although human-associated microbial communities are generally stable, they can altered by common actions experiences. Enteric bacteria, commensal, pathogenic microorganisms, have a major impact on immune system, brain development, behavior, able to produce several neurotransmitters neuromodulators serotonin, kynurenine, catecholamine, etc., well amyloids. However, destructive mechanisms, lead dementia AD, start with microbiome dysbiosis, development local systemic inflammation, dysregulation gut-brain axis. Increased permeability epithelial barrier results invasion different viruses, their neuroactive products support neuroinflammatory reactions It seems that, inflammatory-infectious hypothesis great role microbiome, starts gently push into shadow amyloid cascade has dominated decades. is strongly postulated AD begin gut, closely related imbalance microbiota. This promising area therapeutic intervention. Modulation microbiota through personalized diet or beneficial intervention, alter partners including protein, will probably become new treatment AD.

Язык: Английский

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Modeling Alzheimer’s disease with iPSC-derived brain cells

Molecular Psychiatry, Год журнала: 2019, Номер 25(1), С. 148 - 167

Опубликована: Авг. 7, 2019

Alzheimer’s disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent models yet failed to benefit human patients. While hope remains that earlier intervention existing will improve outcomes, it becoming increasingly clear new approaches understand and combat the pathophysiology of are needed. Human induced pluripotent stem cell (iPSC) technologies changed face preclinical research iPSC-derived types being utilized study an array conditions, including disease. All major brain can now be differentiated from iPSCs, while complex co-culture systems developed facilitate neuroscience research. Many cellular functions perturbed recapitulated using cells vitro, platforms beginning yield insights into interactions occur between during neurodegeneration. Further, iPSC-based genome editing tools critical understanding roles numerous genes mutations found modify risk past decade. still their relative infancy, these developing hold considerable promise push forward efforts other disorders.

Язык: Английский

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The role of CREB and BDNF in neurobiology and treatment of Alzheimer's disease

Life Sciences, Год журнала: 2020, Номер 257, С. 118020 - 118020

Опубликована: Июнь 27, 2020

Язык: Английский

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Age-Related Hearing Loss

Cold Spring Harbor Perspectives in Medicine, Год журнала: 2018, Номер 9(8), С. a033217 - a033217

Опубликована: Окт. 5, 2018

Michael R. Bowl1 and Sally J. Dawson2 1Mammalian Genetics Unit, MRC Harwell Institute, Oxford OX11 0RD, United Kingdom 2UCL Ear University College London, London WC1X 8EE, Correspondence: sally.dawson{at}ucl.ac.uk

Язык: Английский

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Alzheimer’s Disease: An Updated Overview of Its Genetics

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3754 - 3754

Опубликована: Фев. 13, 2023

Alzheimer’s disease (AD) is the most common neurodegenerative in world. It classified as familial and sporadic. The dominant or autosomal presentation represents 1–5% of total number cases. categorized early onset (EOAD; <65 years age) presents genetic mutations presenilin 1 (PSEN1), 2 (PSEN2), Amyloid precursor protein (APP). Sporadic AD 95% cases late-onset (LOAD), occurring patients older than 65 age. Several risk factors have been identified sporadic AD; aging main one. Nonetheless, multiple genes associated with different neuropathological events involved LOAD, such pathological processing beta (Aβ) peptide Tau protein, well synaptic mitochondrial dysfunctions, neurovascular alterations, oxidative stress, neuroinflammation, among others. Interestingly, using genome-wide association study (GWAS) technology, many polymorphisms LOAD identified. This review aims to analyze new findings that are closely related pathophysiology AD. Likewise, it analyzes date through GWAS a high low developing this neurodegeneration. Understanding variability will allow for identification biomarkers opportune therapeutic targets

Язык: Английский

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The Role of Porphyromonas gingivalis Outer Membrane Vesicles in Periodontal Disease and Related Systemic Diseases

Frontiers in Cellular and Infection Microbiology, Год журнала: 2021, Номер 10

Опубликована: Янв. 28, 2021

Periodontal disease is a chronic infectious associated with variety of bacteria, which can cause damage to the periodontal support structure and affect systemic system diseases such as cancer, cardiovascular disease, diabetes, rheumatoid arthritis, non-alcoholic fatty liver, Alzheimer’s disease. Porphyromonas gingivalis ( P. ) most important pathogenic bacteria for It produce outer membrane vesicles (OMVs) release them into environment, playing an role in its pathogenesis. This article focuses on OMVs, reviews production regulation, virulence components, mode action related diseases, view providing new ideas prevention treatment infections.

Язык: Английский

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The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer’s Disease: A Systematic Review

Journal of Clinical Medicine, Год журнала: 2020, Номер 9(2), С. 495 - 495

Опубликована: Фев. 11, 2020

The evidence of a connection between the peripheral inflammatory processes and neurodegenerative diseases central nervous system is becoming more apparent. This review related literature highlights most recent clinical, epidemiological, in vitro studies trying to investigate possible connections periodontal bacteria onset progression Alzheimer's disease. was conducted by searching databases such as PubMed Scopus using keywords or combinations Disease AND dementia periodontitis OR periodontal. After eliminating overlaps screening articles not these issues, we identified 1088 records proceeded selection for an evaluation associative assumptions. hypothesis suggested authors confirmed that bacterial load process linked disease can intensify inflammation at level system, favoring occurrence analysis how directly contribute environment introduction indirect pathogenic proinflammatory cytokines locally produced following colonization defects.

Язык: Английский

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Dysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer’s Disease Pathogenesis

Frontiers in Aging Neuroscience, Год журнала: 2019, Номер 11

Опубликована: Ноя. 20, 2019

Neurons are highly specialized postmitotic cells that inherently dependent on mitochondria owing to their high bioenergetic demand. Mitochondrial dysfunction is therefore associated with various age-related neurodegenerative disorders such as Alzheimer's disease (AD), wherein accumulation of damaged and dysfunctional has been reported early symptoms further contributing progression. In AD, impairment mitochondrial function causes deficiency, intracellular calcium imbalance oxidative stress thereby aggravating the effect Aβ tau pathologies, leading synaptic dysfunction, cognitive memory loss. Although there reports suggesting intricate parallelism between AD pathologies A aggregation hyperphosphorylated accumulation, factors drive pathogenesis either unclear. addition, emerging evidence suggests quality control (QC) mechanisms mitophagy impaired in AD. As an important QC mechanism, plays a critical role maintaining neuronal health function. Studies show different proteins involved mitophagy, dynamics biogenesis affected The compromised may also be attributed autophagosome-lysosome fusion defects lysosomal acidification. Therapeutic interventions aiming restore functions can used strategy for ameliorating pathogenesis. Recent implicates microglial activation via induction reducing amyloid plaque load. This review summarizes current developments field

Язык: Английский

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An update on the utility and safety of cholinesterase inhibitors for the treatment of Alzheimer’s disease

Expert Opinion on Drug Safety, Год журнала: 2020, Номер 19(2), С. 147 - 157

Опубликована: Янв. 24, 2020

Introduction: Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders with a prevalence in US about 5.7 million 2018. With burden projected to increase dramatically coming years, it imperative review current available treatment regimens for their safety and utility. The cholinesterase inhibitors (ChEIs) have continued play pivotal role managing symptoms possibly slowing rate progression AD since 1993. Owing being mainstay AD, efficacy prescribing these drugs needs be reviewed often, especially approval new formulations doses.Areas covered: three ChEIs currently approved by FDA are donepezil, rivastigmine galantamine. This article will tolerability analyze potential modifying properties drugs. authors all recent literature including articles, meta-analyzes, clinical trials more.Expert opinion: These differ subtly mechanisms action, FDA-approved indications. All considered first-line, symptomatic treatments various phases may even potentially disease-modifying effects.

Язык: Английский

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