Revisiting the neuroinflammation hypothesis in Alzheimer’s disease: a focus on the druggability of current targets

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 9, 2023

Alzheimer’s disease (AD) is the most common form of neurodegenerative and disability in elderly; it estimated to account for 60%–70% all cases dementia worldwide. The relevant mechanistic hypothesis explain AD symptoms neurotoxicity induced by aggregated amyloid-β peptide (Aβ) misfolded tau protein. These molecular entities are seemingly insufficient as a multifactorial characterized synaptic dysfunction, cognitive decline, psychotic symptoms, chronic inflammatory environment within central nervous system (CNS), activated microglial cells, dysfunctional gut microbiota. discovery that neuroinflammatory linked innate immunity phenomena started early nineties several authors, including ICC´s group described, 2004, role IL-6 AD-type phosphorylation protein deregulating cdk5/p35 pathway. “Theory Neuroimmunomodulation”, published 2008, proposed onset progression degenerative diseases multi-component “damage signals” phenomena, suggesting feasibility “multitarget” therapies AD. This theory explains detail cascade events stemming from disorder through overactivation Cdk5/p35 All these knowledge have led rational search druggable targets against accumulated evidence on increased levels markers cerebrospinal fluid (CSF) patients, along with reports describing CNS alterations caused senescent immune cells neuro-degenerative diseases, set out conceptual framework which neuroinflammation being challenged different angles towards developing new current points controversial findings therapeutic candidates treat In this article, we discuss neuroimmune-modulatory perspective pharmacological exploration AD, well potential deleterious effects modifying brain parenchyma. We specifically focus B T immuno-senescence, lymphatic (BLS), gut-brain axis alterations, interactions between neurons, microglia astrocytes. also outline identifying “druggable” multi-mechanistic small molecules

Language: Английский

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The Dual Role of Amyloid Beta-Peptide in Oxidative Stress and Inflammation: Unveiling Their Connections in Alzheimer’s Disease Etiopathology

Antioxidants, Journal Year: 2024, Volume and Issue: 13(10), P. 1208 - 1208

Published: Oct. 8, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and it currently the seventh leading cause of death worldwide. It characterized by extracellular aggregation amyloid β-peptide (Aβ) into oligomers fibrils that synaptotoxicity neuronal death. Aβ exhibits dual role in promoting oxidative stress inflammation. This review aims to unravel intricate connection between these processes their contribution AD progression. The delves AD, focusing on involvement metals, mitochondrial dysfunction, biomolecule oxidation. distinct yet overlapping concept nitro-oxidative also discussed, detailing roles nitric oxide, perturbations, cumulative impact production neurotoxicity. Inflammation examined through astroglia microglia function, elucidating response within brain. blood-brain barrier oligodendrocytes are considered context pathophysiology. We current diagnostic methodologies emerging therapeutic strategies aimed at mitigating inflammation, thereby offering potential treatments for halting or slowing comprehensive synthesis underscores pivotal bridging advancing our understanding informing future research treatment paradigms.

Language: Английский

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Selenium Nanoparticles in Protecting the Brain from Stroke: Possible Signaling and Metabolic Mechanisms

Nanomaterials, Journal Year: 2024, Volume and Issue: 14(2), P. 160 - 160

Published: Jan. 11, 2024

Strokes rank as the second most common cause of mortality and disability in human population across world. Currently, available methods treating or preventing strokes have significant limitations, primarily need to use high doses drugs due presence blood-brain barrier. In last decade, increasing attention has been paid capabilities nanotechnology. However, vast majority research this area is focused on mechanisms anticancer antiviral effects nanoparticles. our opinion, not enough neuroprotective nanomaterials. review, we attempted summarize key molecular brain cell damage during ischemia. We discussed current literature regarding various nanomaterials for treatment strokes. examined features all known nanomaterials, possibility which are currently being studied regard, positive negative properties identified. Particular review was nanoselenium since selenium a vital microelement part very important little-studied proteins, e.g., selenoproteins selenium-containing proteins. An analysis modern studies cytoprotective made it possible establish acute chronic protective aimed combine information action nanoparticles neurodegenerative processes, especially cerebral

Language: Английский

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Alpha-synuclein pathology is associated with astrocyte senescence in a midbrain organoid model of familial Parkinson's disease

Molecular and Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 128, P. 103919 - 103919

Published: Feb. 1, 2024

Parkinson's disease (PD) is a complex, progressive neurodegenerative characterized by the loss of dopaminergic neurons in substantia nigra pars compacta midbrain. Despite extensive research efforts, molecular and cellular changes that precede neurodegeneration PD are poorly understood. To address this, here we describe use patient specific human midbrain organoids harboring SNCA triplication to investigate mechanisms underlying degeneration. Our organoid model recapitulates key pathological hallmarks PD, including aggregation α-synuclein neurons. We found these associated with an increase senescence phenotypes astrocytes nuclear lamina defects, presence heterochromatin foci, upregulation cell cycle arrest genes. These results suggest role inducing astrosenescence which may, turn, vulnerability

Language: Английский

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Astroglial Cells: Emerging Therapeutic Targets in the Management of Traumatic Brain Injury

Cells, Journal Year: 2024, Volume and Issue: 13(2), P. 148 - 148

Published: Jan. 12, 2024

Traumatic Brain Injury (TBI) represents a significant health concern, necessitating advanced therapeutic interventions. This detailed review explores the critical roles of astrocytes, key cellular constituents central nervous system (CNS), in both pathophysiology and possible rehabilitation TBI. Following injury, astrocytes exhibit reactive transformations, differentiating into pro-inflammatory (A1) neuroprotective (A2) phenotypes. paper elucidates interactions with neurons, their role neuroinflammation, potential for exploitation. Emphasized strategies encompass utilization endocannabinoid calcium signaling pathways, hormone-based treatments like 17β-estradiol, biological therapies employing anti-HBGB1 monoclonal antibodies, gene therapy targeting Connexin 43, innovative technique astrocyte transplantation as means to repair damaged neural tissues.

Language: Английский

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Astrocyte senescence-like response related to peripheral nerve injury-induced neuropathic pain

Cellular & Molecular Biology Letters, Journal Year: 2023, Volume and Issue: 28(1)

Published: Aug. 15, 2023

Peripheral nerve damage causes neuroinflammation, which plays a critical role in establishing and maintaining neuropathic pain (NeP). The mechanisms contributing to neuroinflammation remain poorly elucidated, pharmacological strategies for NeP are limited. Thus, this study, we planned explore the possible link between astrocyte senescence disorders following chronic sciatic injury.An animal model was established by inducing constrictive injury (CCI) adult rats. A senolytic drug combination of dasatinib quercetin gavaged daily from first postoperative day until end study. Paw mechanical withdrawal threshold (PMWT) paw thermal latency (PTWL) were evaluated assess behaviors response experimental Senescence-associated β-galactosidase staining, western blot analysis, immunofluorescence applied examine levels proinflammatory factors severity senescence-like spinal cord. Lipopolysaccharide (LPS) administered induce astrocytes primary cultures vitro, potential impacts on secretion factors. Furthermore, single-cell RNA sequencing (scRNA-seq) conducted identify senescence-related molecular responses under pain.Following CCI, rats exhibited reduced PMWT PTWL, increased factors, an enhanced degree astrocytes. Treatment with effectively attenuated mitigated hypersensitivities subjected CCI. Mechanistically, dasatinib-quercetin reversed LPS-stimulated cultured decreased scRNA-seq data revealed four genes population, expression clusterin (CLU) protein validated via vitro experiments.The findings indicate peripheral injury, suggest that targeting CLU activation might provide novel therapeutic strategy treat NeP.

Language: Английский

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Effects of High-Fat and High-Fat High-Sugar Diets in the Anxiety, Learning and Memory, and in the Hippocampus Neurogenesis and Neuroinflammation of Aged Rats

Nutrients, Journal Year: 2023, Volume and Issue: 15(6), P. 1370 - 1370

Published: March 11, 2023

High-caloric diets induce several deleterious alterations in the human body, including brain. However, information on effects of these elderly brain is scarce. Therefore, we studied 2 months treatment with high-fat (HF) and high-fat-high-sugar (HFHS) aged male Wistar rats at 18 months. Anxiety levels were analyzed using open-field plus-maze tests, while learning memory processes Morris water maze test. We also neurogenesis doublecortin (DCX) neuroinflammation glial fibrillary acidic protein (GFAP). In rats, HFHS diet impaired spatial learning, memory, working increased anxiety levels, associated a reduction number DCX cells an increase GFAP hippocampus. contrast, HF lighter, impairing Thus, our results suggest that are highly susceptible to high-caloric diets, even if they only started elderly, impact cognition emotions. Furthermore, rich saturated fats sugar more detrimental than are.

Language: Английский

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Polystyrene Nano- and Microplastic Particles Induce an Inflammatory Gene Expression Profile in Rat Neural Stem Cell-Derived Astrocytes In Vitro

Nanomaterials, Journal Year: 2024, Volume and Issue: 14(5), P. 429 - 429

Published: Feb. 27, 2024

Microplastics are considered an emerging environmental pollutant due to their ubiquitous presence in the environment. However, potential impact of microplastics on human health warrants further research. Recent studies have reported neurobehavioral and neurotoxic effects marine rodent models; however, underlying cellular physiology mammals remains unclear. Herein, we exposed neural stem cells cell-derived astrocytes, oligodendrocytes, neurons various sizes concentrations polystyrene nano- microplastics. We investigated uptake, cytotoxicity, alteration gene expression through transcriptome profiling. The cell type most affected by decreased viability were astrocytes after 7 days repeated exposure. Transcriptional analysis showed that 1274 genes differentially expressed 500 nm microplastics, but only 531 altered 50 nanoplastics. Both canonical pathway Kyoto Encyclopedia Genes Genomes upregulated pathways involved neuroinflammation, innate adaptive immunity, migration, proliferation, extracellular matrix remodeling, cytoskeleton structures. downregulated lipid metabolism, specifically fatty acid oxidation cholesterol metabolism. Our results show repeatedly for undergo changes hallmarks astrogliosis.

Language: Английский

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Chemically Functionalized Single-Walled Carbon Nanotubes Prevent the Reduction in Plasmalemmal Glutamate Transporter EAAT1 Expression in, and Increase the Release of Selected Cytokines from, Stretch-Injured Astrocytes in Vitro

Cells, Journal Year: 2024, Volume and Issue: 13(3), P. 225 - 225

Published: Jan. 25, 2024

We tested the effects of water-soluble single-walled carbon nanotubes, chemically functionalized with polyethylene glycol (SWCNT-PEG), on primary mouse astrocytes exposed to a severe in vitro simulated traumatic brain injury (TBI). The application SWCNT-PEG culture media injured did not affect cell damage levels, when compared those obtained from injured, functionalization agent (PEG)-treated cells. Furthermore, change levels oxidatively damaged proteins astrocytes. However, this nanomaterial prevented reduction plasmalemmal glutamate transporter EAAT1 expression caused by injury, rendering level par that control, uninjured PEG-treated astrocytes; parallel, there was no significant GFAP. Additionally, increased release selected cytokines are generally considered be involved recovery processes following injuries. As loss EAATs has been implicated as culprit suffering human patients TBI, could have valuable at site, preventing astrocytic and consequently allowing for much-needed uptake extracellular space, accumulation which leads unwanted excitotoxicity. Additional potential therapeutic benefits reaped fact stimulated astrocytes, would promote after thus counteract excess proinflammatory present TBI.

Language: Английский

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Role of Senescent Astrocytes in Health and Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8498 - 8498

Published: May 9, 2023

For many decades after their discovery, astrocytes, the abundant glial cells of brain, were believed to work as a glue, supporting structure and metabolic functions neurons. A revolution that started over 30 years ago revealed additional these cells, including neurogenesis, gliosecretion, glutamate homeostasis, assembly function synapses, neuronal metabolism with energy production, others. These properties have been confirmed, limited however, proliferating astrocytes. During aging or following severe brain stress lesions, astrocytes are converted into no-longer-proliferating, senescent forms, similar in morphology but profoundly modified functions. The changed specificity is largely due altered gene expression. ensuing effects include downregulation typical upregulation others, concerned neuroinflammation, release pro-inflammatory cytokines, dysfunction etc., specific senescence program. decrease support protection by induces development, vulnerable regions, toxicity together cognitive decline. Similar changes, ultimately reinforced astrocyte aging, also induced traumatic events molecules involved dynamic processes. Senescent play critical roles development diseases. first demonstration, obtained for Alzheimer’s disease less than 10 ago, contributed elimination previously predominant neuro-centric amyloid hypothesis. initial effects, operating considerable time before appearance known symptoms evolve severity up proliferation during final outcome. Involvement other neurodegenerative diseases cancer now intensely investigated.

Language: Английский

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