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

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Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions

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

Published: Feb. 21, 2023

Abstract Parkinson’s disease (PD) is the second most common neurodegenerative worldwide, and its treatment remains a big challenge. The pathogenesis of PD may be related to environmental genetic factors, exposure toxins gene mutations beginning brain lesions. identified mechanisms include α-synuclein aggregation, oxidative stress, ferroptosis, mitochondrial dysfunction, neuroinflammation, gut dysbiosis. interactions among these molecular complicate pose great challenges drug development. At same time, diagnosis detection are also one obstacles due long latency complex mechanism. Most conventional therapeutic interventions for possess limited effects have serious side effects, heightening need develop novel treatments this disease. In review, we systematically summarized pathogenesis, especially PD, classical research models, clinical diagnostic criteria, reported therapy strategies, as well newly candidates in trials. We shed light on components derived from medicinal plants that their treatment, with expectation provide summary outlook developing next generation drugs preparations therapy.

Language: Английский

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Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Journal of Parkinson s Disease, Journal Year: 2020, Volume and Issue: 11(1), P. 45 - 60

Published: Oct. 13, 2020

Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from observation that mitochondrial toxins cause PD, findings genetic PD supported contribution to disease. Here, proteins encoded by autosomal recessively inherited genes Parkin, PTEN-induced kinase 1 (PINK1), DJ-1 are involved pathways. Additional evidence for stems models autosomal-dominant due mutations alpha-synuclein (SNCA) leucine-rich repeat 2 (LRRK2). Moreover, patients harboring alterations polymerase gamma (POLG) often exhibit signs parkinsonism. While some molecular studies suggest is primary event others speculate it result impaired clearance. Most recent research even implicated damage-associated patterns released non-degraded mitochondria neuroinflammatory processes PD. we summarize manifold literature dealing with context light advances field personalized medicine, patient stratification according degree impairment followed enhancement therapy may hold potential at least subset cases. Thus, second part this review, discuss therapeutic approaches targeting aim prevent or delay neurodegeneration

Language: Английский

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The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Aug. 13, 2021

Ageing is an inevitable event in the lifecycle of all organisms, characterized by progressive physiological deterioration and increased vulnerability to death. has also been described as primary risk factor most neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s (PD), Huntington’s (HD), frontotemporal lobar dementia (FTD). These diseases occur more prevalently aged populations. Few effective treatments have identified treat these epidemic neurological crises. Neurodegenerative are associated with enormous socioeconomic personal costs. Here, pathogenesis AD, PD, other presented, a summary their known associations biological hallmarks ageing: genomic instability, telomere attrition, epigenetic alterations, loss proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion, altered intercellular communications. Understanding central mechanisms that underlie ageing important for identifying novel therapeutic targets diseases. Potential strategies, use NAD + precursors, mitophagy inducers, inhibitors discussed.

Language: Английский

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Prussian Blue Nanozyme as a Pyroptosis Inhibitor Alleviates Neurodegeneration

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(15)

Published: Feb. 10, 2022

Current pharmacological interventions for Parkinson's disease (PD) remain unsatisfactory in clinical settings. Inflammasome-mediated pyroptosis represents a potential therapeutic target the alleviation of neurodegenerative diseases. The development inflammasome-mediated agonists or antagonists may transform treatment However, identification specific compounds that inhibit remains challenging. Herein, Prussian blue nanozyme (PBzyme) is revealed as inhibitor to alleviate neurodegeneration mouse and cell models PD. PBzyme protects microglia neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). alleviates motor deficits, attenuates damage mitochondrial membrane potential, rescues dopaminergic neurons. Furthermore, intra-cerebroventricular injection reduces degeneration inhibits neuroinflammation an MPTP-induced PD model. Both vitro vivo results demonstrate activation microglial nucleotide-binding domain leucine-rich repeat family pyrin containing 3 (NLRP3) inflammasomes caspase-1 by scavenging reactive oxygen species, thereby downregulating gasdermin D (GSDMD) cleavage well inflammatory factor production, eventually leading inhibition pyroptosis. Overall, this work highlights neuroprotective effects provides valuable mechanistic insights strategy

Language: Английский

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Andrographolide suppresses NLRP3 inflammasome activation in microglia through induction of parkin-mediated mitophagy in in-vitro and in-vivo models of Parkinson disease

Brain Behavior and Immunity, Journal Year: 2020, Volume and Issue: 91, P. 142 - 158

Published: Sept. 22, 2020

Language: Английский

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Dopamine, Immunity, and Disease

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 75(1), P. 62 - 158

Published: Dec. 8, 2022

The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions peripheral organs, such as blood pressure, renal activity, intestinal motility. Beyond these functions, growing body of evidence indicates that an important immunoregulatory factor. Most types immune cells express receptors other dopaminergic proteins, take up, produce, store, and/or release dopamine, suggesting immunomodulation for function. Targeting pathways could be promising avenue the treatment inflammation disease, but despite increasing research this area, data on specific effects disease remain inconsistent poorly understood. Therefore, review integrates current knowledge role cell function inflammatory signaling across systems. We discuss understanding regulation CNS tissues, highlighting diseases Parkinson’s several neuropsychiatric conditions, neurologic human immunodeficiency virus, bowel rheumatoid arthritis, others. Careful consideration given to influence experimental design results, we note number areas need further research. Overall, our immunology at cellular, tissue, level prompts development therapeutics strategies targeted toward ameliorating through immunity.

Significance Statement

Canonically, recognized involved cognition, reward. However, acts modulator periphery. This comprehensively assesses pathogenesis cellular tissue level. will provide broad access information fields, identify investigation, drive therapeutic strategies.

Language: Английский

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Neurodegenerative Disease and the NLRP3 Inflammasome

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: March 10, 2021

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by progressive neuronal loss the brain or peripheral nervous system, generally involve protein aggregation, as well metabolic abnormalities immune dysregulation. Although vast majority neurodegeneration idiopathic, there many known genetic environmental triggers. In past decade, research exploring low-grade systemic inflammation its impact on development progression increased. A particular focus been whether arises only secondary effect also cause pathology. inflammasomes, more specifically NLRP3 inflammasome, crucial component innate usually activated response infection tissue damage. Dysregulation inflammasome implicated several disorders, such Alzheimer’s disease, Parkinson’s Huntington’s amyotrophic lateral sclerosis, prion diseases. This review aims summarise current literature role pathogenesis diseases, work investigating inhibition potential future therapy.

Language: Английский

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The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Redox Biology, Journal Year: 2021, Volume and Issue: 47, P. 102134 - 102134

Published: Sept. 22, 2021

Parkinson's disease (PD) is a chronic neurodegenerative disorder that characterized by motor symptoms as result of loss dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied neuroinflammation, oxidative stress, formation α-synuclein aggregates. Celastrol, potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged neuroprotective agent. However, mechanisms which celastrol PD remain elusive. Here we show protects against dopamine neuron loss, mitigates relieves deficits MPTP-induced mouse model AAV-mediated human overexpression model. Whole-genome deep sequencing analysis revealed Nrf2, NLRP3 caspase-1 SNc may be associated with actions PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO Caspase-1-KO), identified inhibits inflammasome activation, nigrostriatal degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest axis serve key target treatment, highlight favorable properties for neuroprotection, making promising disease-modifying agent

Language: Английский

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Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson’s Disease

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 8, 2021

According to emerging studies, the excessive activation of microglia and subsequent release pro-inflammatory cytokines play important roles in pathogenesis progression Parkinson’s disease (PD). However, exact mechanisms governing chronic neuroinflammation remain elusive. Findings demonstrate an elevated level NLRP3 inflammasome activated substantia nigra PD patients. Activated aggravates pathology accelerates neurodegenerative diseases. Abnormal protein aggregation α-synuclein (α-syn), a pathologically relevant PD, were reported activate through interaction with toll-like receptors (TLRs). This eventually releases translocation nuclear factor kappa-B (NF-κB) causes impairment mitochondria, thus damaging dopaminergic neurons. Currently, therapeutic drugs for are primarily aimed at providing relief from its clinical symptoms, there no well-established strategies halt or reverse this disease. In review, we update existing knowledge on role α-syn/TLRs/NF-κB/NLRP3 axis microglial PD. addition, review summarizes recent progress as potential target treatment by inhibiting activation.

Language: Английский

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