Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Cells, Journal Year: 2020, Volume and Issue: 9(7), P. 1687 - 1687

Published: July 14, 2020

Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from substantia nigra pars compacta. Although molecular bases for PD development are still little defined, extensive evidence human samples and animal models support involvement inflammation in onset or progression. However, exact trigger this response remains unclear. Here, we provide systematic review cellular mediators, i.e., microglia, astroglia endothelial cells. We also discuss genetic transcriptional control immunomodulatory role dopamine reactive oxygen species. Finally, summarize preclinical clinical approaches targeting neuroinflammation PD.

Language: Английский

---

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Language: Английский

---

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

Antioxidants, Journal Year: 2020, Volume and Issue: 9(8), P. 647 - 647

Published: July 22, 2020

Oxidative stress develops as a response to injury and reflects breach in the cell’s antioxidant capacity. Therefore, fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving homeostasis. Mitochondria are major source an immediate target ROS. Under different stimuli, including oxidative impaired quality control, mitochondrial constituents (e.g., DNA, mtDNA) displaced toward intra- or extracellular compartments. However, mechanisms responsible mtDNA unloading remain largely unclear. While shuttling freely within cell, can be delivered into compartment via either extrusion entire nucleoids release vesicles. Once discarded, may act damage-associated molecular pattern (DAMP) trigger innate immune inflammatory by binding danger-signal receptors. Neuroinflammation associated with large array neurological disorders which DAMPs could represent common thread supporting disease progression. The exploration non-canonical pathways involved control neurodegeneration unveil novel targets development therapeutic agents. Here, we discuss these processes setting two neurodegenerative diseases (Alzheimer’s Parkinson’s disease) Down syndrome, most frequent progeroid syndrome.

Language: Английский

---

Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

Cell, Journal Year: 2021, Volume and Issue: 184(20), P. 5089 - 5106.e21

Published: Sept. 1, 2021

Microglia jointly degrade fibrillar

Language: Английский

---

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

---

Periphery and brain, innate and adaptive immunity in Parkinson’s disease

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(4), P. 527 - 545

Published: Feb. 8, 2021

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder where alpha-synuclein plays central role in the death and dysfunction of neurons, both, central, as well peripheral nervous system. Besides neuronal events observed patients, PD also includes significant immune component. It suggested that PD-associated response will have consequences on health, thus opening immunomodulation potential therapeutic strategy PD. The changes during occur brain, involving microglia, but periphery with cells innate system, particularly monocytes, those adaptive immunity, such T-cells. This realization arises from multiple patient studies, data animal models disease, providing strong evidence for system crosstalk Here we review showing crucial activation We describe studies suggesting inflammation early develop dynamically through time contributing to degeneration symptomatology patients. novel finding has contributed definition multisystem should be approached more integratory manner rather than brain-focused classical approach.

Language: Английский

---

The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options

Brain, Journal Year: 2021, Volume and Issue: 144(9), P. 2571 - 2593

Published: April 12, 2021

Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with shows unique changes, be used as early biomarkers disease. Alterations the composition related cause or effect non-motor symptoms, but specific pathogenic mechanisms are unclear. and its metabolites have been suggested involved pathogenesis by regulating neuroinflammation, barrier function neurotransmitter activity. There bidirectional communication between enteric nervous system CNS, microbiota-gut-brain axis provide pathway for transmission α-synuclein. We highlight recent discoveries about alterations focus on current mechanistic insights into pathophysiology. Moreover, we discuss interactions production α-synuclein inflammation neuroinflammation. In addition, draw attention diet modification, use probiotics prebiotics faecal transplantation potential therapeutic approaches that lead new treatment paradigm

Language: Английский

---

Microglia Mediated Neuroinflammation in Parkinson’s Disease

Cells, Journal Year: 2023, Volume and Issue: 12(7), P. 1012 - 1012

Published: March 25, 2023

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder seen, especially in elderly. Tremor, shaking, movement problems, and difficulty with balance coordination are among hallmarks, dopaminergic neuronal loss substantia nigra pars compacta of brain aggregation intracellular protein α-synuclein pathological characterizations. Neuroinflammation has emerged as an involving mechanism at initiation development PD. It a complex network interactions comprising immune non-immune cells addition to mediators response. Microglia, resident macrophages CNS, take on leading role regulating neuroinflammation maintaining homeostasis. Under normal physiological conditions, they exist “homeostatic” but upon stimuli, switch “reactive state”. Pro-inflammatory (M1) anti-inflammatory (M2) phenotypes used classify microglial activity each phenotype having its own markers released mediators. When M1 microglia persistent, will contribute various inflammatory diseases, including such In this review, we focus mediated PD also signaling pathways, receptors, involved process, presenting studies that associate microglia-mediated inflammation A better understanding important seeking new therapies for possibly other diseases.

Language: Английский

---

Association of NO₂ and Other Air Pollution Exposures With the Risk of Parkinson Disease

JAMA Neurology, Journal Year: 2021, Volume and Issue: 78(7), P. 800 - 800

Published: May 17, 2021

Importance

The development of Parkinson disease (PD) may be promoted by exposure to air pollution.

Objective

To investigate the potential association between particulate matters (PM_2.5and PM₁₀), nitrogen dioxide (NO₂), ozone (O₃), sulfur (SO₂), and carbon monoxide (CO) risk incident PD.

Design, Setting, Participants

This retrospective cohort study used data from Korean National Health Insurance Service. Among 1 021 208 individuals in database, those who had lived Seoul January 2002 December 2006 (n = 176 875) were screened for eligibility. A total 78 830 adults older than 40 years without PD included this study. Individuals diagnosed with before 159) or younger 97 886) excluded. Each participant was followed up annually 2007 2015, thereby adding 757 704 person-years follow-up. Data analyzed September 2020.

Exposures

Individual levels PM_2.5, PM₁₀, NO₂, O₃, SO₂, CO estimated based on participants’ residential address at district level. evaluate long-term pollution, time-varying 5-year mean pollutant calculated each participant.

Main Outcomes Measures

outcome measure pollution measured as hazard ratios after adjusting demographic factors, socioeconomic medical comorbidities.

Results

At baseline, (SD) age participants 54.4 (10.7) years, 41 070 (52.1%) female. 338 newly identified during period. Exposure NO₂was associated an increase (hazard ratio highest vs lowest quartile, 1.41; 95% CI, 1.02-1.95;Pfor trend .045). No statistically significant associations PM_2.5,PM₁₀, incidence found.

Conclusions Relevance

In large study, a NO₂exposure identified. finding suggests role pollutants development, advocating need implement targeted public health policy.

Language: Английский

---

Neuroinflammation, Microglia and Implications for Retinal Ganglion Cell Survival and Axon Regeneration in Traumatic Optic Neuropathy

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: March 4, 2022

Traumatic optic neuropathy (TON) refers to a pathological condition caused by direct or indirect insult the nerves, which often leads partial permanent vision deficit due massive loss of retinal ganglion cells (RGCs) and their axonal fibers. Retinal microglia are immune-competent residing in retina. In rodent models nerve crush (ONC) injury, resident gradually become activated, form end-to-end alignments vicinity degenerating RGC axons, actively internalized them. Some activated adopt an amoeboid morphology that engulf dying RGCs after ONC. injured nerve, contribute myelin debris clearance at lesion site. However, phagocytic capacity is extremely poor therefore cellular largely ineffective. The presence growth-inhibitory glial scar formed reactive astrocytes inhibit regeneration accounts for visual function recovery patients with TON. this Review, we summarize current understanding survival axon Resident play key role facilitating Wallerian degeneration subsequent they also responsible producing pro-inflammatory cytokines, chemokines, oxygen species possess neurotoxic effects on RGCs. Intraocular inflammation triggers influx blood-borne myeloid produce oncomodulin promote regeneration. intraocular induces chronic neuroinflammation exacerbates secondary tissue damages limits Activated required proliferation oligodendrocyte precursor (OPCs); however, sustained activation suppress differentiation OPCs into mature oligodendrocytes remyelination injury. Collectively, controlled infiltrating facilitate repair. Recent advance single-cell RNA-sequencing identification microglia-specific markers could improve our microglial biology development novel therapeutic strategies aiming switch microglia’s phenotype foster neuroprotection.

Language: Английский

---