Microglia affect α-synuclein cell-to-cell transfer in a mouse model of Parkinson’s disease DOI Creative Commons
Sonia George, Nolwen L. Rey,

Trevor Tyson

et al.

Molecular Neurodegeneration, Journal Year: 2019, Volume and Issue: 14(1)

Published: Aug. 16, 2019

Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute the pathogenesis Parkinson's disease (PD) and underlie spread α-syn neuropathology. Increased pro-inflammatory cytokine levels activated microglia are present in PD can promote aggregation. However, it unclear how influence cell-to-cell transfer. We developed a clinically relevant mouse model monitor prion-like between cells; we transplanted wild-type embryonic midbrain neurons into striatum overexpressing human (huα-syn) following adeno-associated viral injection substantia nigra. In this system, depleted or microglial cells determined effects on transfer huα-syn from host nigrostriatal implanted dopaminergic neurons, using presence within grafted as readout. First, compared mice with normal number which had pharmacologically ablated 80% striatum. With fewer microglia, observed increased accumulation neurons. Second, assessed context by one two stimuli, lipopolysaccharide (LPS) interleukin-4 (IL-4). LPS exposure led strong activation (as morphology, production an upregulation genes involved inflammatory response LPS-injected RNA sequencing analysis). significantly higher amounts contrast, IL-4 did not change proportion dopamine that contained relative controls. As expected, analysis striatal tissue revealed differential gene expression IL-4-injected mice; upregulated injected including several those response. The absence hyperstimulation affected brain. Our results suggest under resting, non-inflammatory conditions, modulate α-syn. Pharmacological regulation neuroinflammation could represent future avenue for limiting

Language: Английский

Ageing as a risk factor for neurodegenerative disease DOI
Yujun Hou, Xiuli Dan, Mansi Babbar

et al.

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(10), P. 565 - 581

Published: Sept. 9, 2019

Language: Английский

Citations

2385
Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes DOI Creative Commons
Hyuk Sung Kwon, Seong‐Ho Koh

Translational Neurodegeneration, Journal Year: 2020, Volume and Issue: 9(1)

Published: Nov. 26, 2020

Abstract Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s and amyotrophic lateral sclerosis. Microglia astrocytes are key regulators of inflammatory responses in the central nervous system. The activation microglia heterogeneous traditionally categorized neurotoxic (M1-phenotype A1-phenotype astrocytes) or neuroprotective (M2-phenotype A2-phenotype astrocytes). However, this dichotomized classification may not reflect various phenotypes astrocytes. relationship between these activated glial cells also very complicated, phenotypic distribution can change, based on progression diseases. A better understanding roles diseases essential for developing effective therapies. In review, we discuss response focusing contributions their relationship. addition, biomarkers to measure neuroinflammation studies therapeutic drugs that modulate neuroinflammation.

Language: Английский

Citations

1650
Hallmarks of neurodegenerative diseases DOI Creative Commons

David M. Wilson,

Mark Cookson, Ludo Van Den Bosch

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(4), P. 693 - 714

Published: Feb. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Language: Английский

Citations

801
Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation DOI
Erik C. B. Johnson, Eric B. Dammer, Duc M. Duong

et al.

Nature Medicine, Journal Year: 2020, Volume and Issue: 26(5), P. 769 - 780

Published: April 13, 2020

Language: Английский

Citations

763
ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease DOI Creative Commons
Dominic S. A. Simpson, Peter L. Oliver

Antioxidants, Journal Year: 2020, Volume and Issue: 9(8), P. 743 - 743

Published: Aug. 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.

Language: Английский

Citations

700
Protein transmission in neurodegenerative disease DOI
Chao Peng, John Q. Trojanowski, Virginia M.‐Y. Lee

et al.

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(4), P. 199 - 212

Published: March 23, 2020

Language: Английский

Citations

475
Glial Cells: Role of the Immune Response in Ischemic Stroke DOI Creative Commons
Shenbin Xu, Jianan Lü, Anwen Shao

et al.

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Feb. 26, 2020

Ischemic stroke, which accounts for 75-80% of strokes, is a predominant cause morbidity and mortality worldwide. Recently, post-stroke immune response becomes new breakthrough the treatment strategy ischemic stroke. Glial cells, including microglia, astrocytes, oligodendrocytes, are major components peri-infarction environment in central nervous system have been elucidated to play critical roles regulation. However, increasing evidences suggest that glial cells exert different, even contrary effect Microglia, survey CNS homostasis regulate innate response, rapidly activated following The microglia would release inflammatory cytokines induce neuronal tissue injuries. On contrary, anti-inflammatory neurotrophic factors secreted by alternatively considered be benefit recovery Astrocytes activation reactive gliosis stroke contribute limitaion brain injury stabalize homeostasis. scar developed astrocytes also hinder reconnectivity extension. Oligodendrocytes shown extensively involved demyelination remyelination after Oligodendrocyte precursor able differentiate into reactived supposed lead functional recovery. Here we discuss mechanisms regulation mediated interaction between neurons. present review, from perspective various describes their possible at different stages future intervention targets.

Language: Английский

Citations

459
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets DOI Creative Commons
Chao Gao, Jingwen Jiang, Yuyan Tan

et al.

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

Citations

426
Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner DOI Creative Commons
Emily F. Willis, Kelli P. A. MacDonald, Quan Nguyen

et al.

Cell, Journal Year: 2020, Volume and Issue: 180(5), P. 833 - 846.e16

Published: March 1, 2020

Language: Английский

Citations

404
Modeling Alzheimer’s disease with iPSC-derived brain cells DOI Creative Commons

Jay Penney,

William T. Ralvenius, Li‐Huei Tsai

et al.

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 25(1), P. 148 - 167

Published: Aug. 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.

Language: Английский

Citations

364