Neuroprotection Against Oxidative Stress: Phytochemicals Targeting TrkB Signaling and the Nrf2-ARE Antioxidant System

Frontiers in Molecular Neuroscience, Journal Year: 2020, Volume and Issue: 13

Published: July 2, 2020

Oxidative stress (OS) plays a critical role in the pathophysiology of several brain-related disorders, including neurodegenerative diseases and ischemic stroke, which are major causes dementia. The Nrf2-ARE (nuclear factor erythroid-2-related 2 (Nrf2)/antioxidant responsive element (ARE) antioxidant) system, primary cellular defense against OS, an essential neuroprotection by regulating expressions antioxidant molecules enzymes. However, simultaneous events resulting overproduction reactive oxygen species (ROS) deregulation system damage cell components cause loss neuron structural functional integrity. On other hand, TrkB (tropomyosin-related kinase B) signaling, classical neurotrophin signaling pathway, regulates neuronal survival synaptic plasticity, play pivotal roles memory cognition. Also, specifically TrkB/PI3K/Akt (TrkB-phosphatidylinositol 3 kinase/protein pathway promotes activation nuclear translocation Nrf2, thus, confers OS. is also known to be downregulated brain disorders due lack support. Therefore, activations offer potential approach design novel therapeutic agents for disorders. Here, we briefly overview development OS association between pathogenesis injury. We propose signaling-mediated systems considered pharmacological targets treatment diseases, review literature on neuroprotective effects phytochemicals that can co-activate these systems.

Language: Английский

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GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: June 30, 2020

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically amyloid plaques, neuronal loss, neurofibrillary tangles. Abnormal β-protein (Aβ) deposition in the brain often thought of as major initiating factor AD neuropathology. However, gamma-aminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, decreases synaptic glutamatergic transmission decrease neural network activity. Furthermore, there now evidence suggesting that activity aberrantly increased patients animal models due functional decreased GABA interneurons, contributing deficits. Here we describe roles played excitatory neurons Aβ-induced how altered regulate We also comprehensively review recent studies on receptors can be exploited for therapeutic benefit. an emerging target AD, with further clinical trials urgently warranted.

Language: Английский

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APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Sept. 24, 2022

Abstract ApoE is the major lipid and cholesterol carrier in CNS. There are three human polymorphisms, apoE2, apoE3, apoE4, genetic expression of APOE4 one most influential risk factors for development late-onset Alzheimer's disease (AD). Neuroinflammation has become third hallmark AD, together with Amyloid-β plaques neurofibrillary tangles hyperphosphorylated aggregated tau protein. This review aims to broadly extensively describe differential aspects concerning apoE. Starting from evolution apoE how APOE's single-nucleotide polymorphisms affect its structure, function, involvement during health disease. reflects on impact critical AD pathology, such as neuroinflammatory response, particularly effect APOE astrocytic microglial function dynamics, synaptic amyloid-β load, autophagy, cell–cell communication. We discuss affecting pathology combined genotype, sex, age, diet, physical exercise, current therapies clinical trials field. The genotype other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, multiple also addressed. Therefore, this gathers relevant findings related up date implications CNS pathologies provide a deeper understanding knowledge

Language: Английский

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Choroid Plexus Volume and Permeability at Brain MRI within the Alzheimer Disease Clinical Spectrum

Radiology, Journal Year: 2022, Volume and Issue: 304(3), P. 635 - 645

Published: May 17, 2022

Background Mounting evidence suggests that the choroid plexus (CP) plays an important role in pathophysiology of Alzheimer disease (AD), but its imaging profile cognitive impairment remains unclear. Purpose To evaluate CP volume, permeability, and susceptibility by using MRI patients at various stages impairment. Materials Methods This retrospective study evaluated with symptoms who underwent 3.0-T brain, including dynamic contrast-enhanced (DCE) quantitative mapping (QSM), between January 2013 May 2020. volume was automatically segmented three-dimensional T1-weighted sequences; transfer constant (ie, Ktrans) fractional plasma Vp) were determined DCE MRI, assessed QSM. The effects expressed as ratio to intracranial on cognition multivariable linear regression adjusted for age, sex, education, apolipoprotein E ε4 allele status, volumetric measures. Results A total 532 (mean 72 years ± 9 [SD]; 388 women) included: 78 subjective (SCI), 158 early mild (MCI), 149 late MCI, 147 AD. Among these, 132 greater more severe (ratio × 103: 0.9 0.3 SCI, 1.0 1.1 1.3 0.4 AD; P < .001). Lower Ktrans (r = -0.19; .03) Vp -0.20; .02) negatively associated volume; not 0.15; .10). memory (B -0.67; standard error mean [SEM], 0.21; .01), executive function -0.90; SEM, 0.31; global -0.82; 0.32; .01). Conclusion symptoms, larger severity spectrum. Published under a CC BY 4.0 license. Online supplemental material is available this article. See also editorial Chiang issue.

Language: Английский

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Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

Frontiers in Cellular Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: July 19, 2021

Amyloid-β (Aβ) is the predominant pathologic protein in Alzheimer's disease (AD). The production and deposition of Aβ are important factors affecting AD progression prognosis. neurotoxic contributes to damage blood-brain barrier. However, BBB also crucial maintaining normal metabolism Aβ, dysfunction aggravates deposition. This review characterizes AD, summarizes their interactions, details respective mechanisms.

Language: Английский

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GABAergic dysfunction, neural network hyperactivity and memory impairments in human aging and Alzheimer’s disease

Seminars in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 116, P. 146 - 159

Published: Feb. 9, 2021

In this review, we focus on the potential role of γ-aminobutyric acidergic (GABAergic) system in age-related episodic memory impairments humans, with a particular Alzheimer's disease (AD). Well-established animal models have shown that GABA plays central regulating and synchronizing neuronal signaling hippocampus, brain area critical for undergoes early significant morphologic functional changes course AD. Neuroimaging research humans has documented hyperactivity hippocampus losses resting state connectivity Default Mode Network, network itself prominently includes hippocampus-presaging decline individuals at-risk Apolipoprotein ε4, highest genetic risk factor AD, is associated GABAergic dysfunction models, humans. combination, these findings suggest may be linchpin complex factors eventually leads to principal clinical hallmark AD: loss. Here, will review current literature supporting hypothesis. First, molecular cellular basis its cognition. Next, report evidence dysregulations AD normal aging, both human studies. Finally, outline model based results neuroimaging studies which hippocampal tasks concurrent even preceding diagnosis, along modulate association.

Language: Английский

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Immunological mechanisms of inflammatory diseases caused by gut microbiota dysbiosis: A review

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 164, P. 114985 - 114985

Published: June 11, 2023

The gut microbiota is indispensable for maintaining host health by enhancing the host's digestive capacity, safeguarding intestinal epithelial barrier, and preventing pathogen invasion. Additionally, exhibits a bidirectional interaction with immune system promotes of to mature. Dysbiosis microbiota, primarily caused factors such as genetic susceptibility, age, BMI, diet, drug abuse, significant contributor inflammatory diseases. However, mechanisms underlying diseases resulting from dysbiosis lack systematic categorization. In this study, we summarize normal physiological functions symbiotic in healthy state demonstrate that when occurs due various external factors, are lost, leading pathological damage lining, metabolic disorders, barrier damage. This, turn, triggers disorders eventually causes systems. These discoveries provide fresh perspectives on how diagnose treat unrecognized variables might affect link between illnesses need further studies extensive basic clinical research will still be required investigate relationship future.

Language: Английский

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The emerging role of exosomes in Alzheimer’s disease

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 68, P. 101321 - 101321

Published: March 14, 2021

Language: Английский

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Periodontal microorganisms and Alzheimer disease – A causative relationship?

Periodontology 2000, Journal Year: 2022, Volume and Issue: 89(1), P. 59 - 82

Published: March 4, 2022

Abstract In the initiation or exacerbation of Alzheimer disease, dissemination oral microorganisms into brain tissue low‐level systemic inflammation have been speculated to play a role. However, impact microorganisms, such as Porphyromonas gingivalis , on pathogenesis disease and potential causative relationship is still unclear. The present review has critically reviewed literature by examining following aspects: (a) microbiome immune response in elderly population, (b) human studies association between periodontal gut (c) animal vitro (d) preventive therapeutic approaches. Factors contributing microbial dysbiosis seem be aging, local inflammation, diseases, wearing dentures, living nursing homes no access adequate hygiene measures. was detectable post‐mortem samples. Microbiome analyses saliva samples biofilms showed decreased diversity different composition compared cognitively healthy subjects. Many in‐vitro underline P induce disease‐related alterations. models, recurring applications its components increased pro‐inflammatory mediators β‐amyloid deteriorated animals' cognitive performance. Since periodontitis result disturbed homoeostasis, an effect therapy host related parameters may suggested should elucidated further clinical trials.

Language: Английский

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Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 144(5), P. 821 - 842

Published: Sept. 6, 2022

Abstract Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by European Alzheimer & Dementia Biobank (EADB), largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total 13,116 individuals (discovery n = 8074; replication 5042 individuals). Besides APOE locus, novel associations two other well-established AD risk loci were observed; CR1 shown locus for Aβ42 BIN1 pTau. GMNC C16orf95 further identified as pTau, which latter is novel. Clustering methods exploring influence all known protein levels, revealed 4 biological categories suggesting multiple pTau related pathways involved etiology AD. In functional follow-up analyses, both associated lateral ventricular volume, implying an overlap genetic brain volume.

Language: Английский

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