Brain alarm by self-extracellular nucleic acids: from neuroinflammation to neurodegeneration
Reiner Kunze,
Silvia Fischer,
Hugo H. Marti
et al.
Abstract:Neurological disorders such as stroke, multiple sclerosis, as well as the neurodegenerative diseases Parkinson's or Alzheimer's disease are accompanied or even powered by danger associated molecular patterns (DAMPs), defined as endogenous molecules released from stressed or damaged tissue. Besides protein-related DAMPs or “alarmins”, numerous nucleic acid DAMPs exist in body fluids, such as cell-free nuclear and mitochondrial DNA as well as different species of extracellular RNA, collectively termed as self-ex… Show more
“…Besides, dopamine-induced extracellular traps (ETs) are functional ( 46 ). There are two main functional regions of NETs present: the generation of oversized NETs scaffolds (consisting of whole decompressed nucDNA, histones, and various antimicrobial proteins and enzymes) used to trap and kill microorganisms in the initial immune response when neutrophils are stimulated; and the other, where activated platelets also act as an inducer of NETosis by providing adhesive interactions with neutrophils, which ultimately results in the immediate formation of cellular aggregates, from which the NETs are released to stimulate prothrombotic functions ( 22 ). Meanwhile, not only neutrophils but also mast cells, eosinophils, basophils, macrophages and also microglial cells as the resident immune cell of the CNS have been described to release nucDNA-containing ETs in response to various stimuli ( 47 , 48 ).…”
Section: Discussionmentioning
confidence: 99%
“…Different types of exDNA such cfDNA or NETs have been identified under various pathophysiological conditions (including hyperinflammation, tumor progression or neurodegeneration) in the brain and can contribute to disease onset and progression in various ways ( 19 – 21 ). A common denominator in the pathogenesis is the release of mtDNA and cfDNA, the latter being particularly available in NETs, whereby both parameters may serve as disease biomarker ( 22 ). At present, studies in neurodegenerative diseases, such as multiple spinal sclerosis ( 23 ) and Alzheimer’s disease ( 24 ) have been investigated in relation to NETs, as well as PD has been reported to demonstrate a link between mtDNA-induced inflammation and PD ( 25 ), while the mechanism of the association with NETs is still unknown.…”
IntroductionNeutrophil extracellular traps (NETs) constitute a crucial element of the immune system, and dysfunction in immune responses is implicated in the susceptibility and progression of Parkinson's disease (PD). Nevertheless, the mechanism connecting PD and NETs remains unclear. This study aims to uncover potential NETs-related immune biomarkers and elucidate their role in PD pathogenesis.MethodsThrough differential gene analysis of PD and NETs in GSE7621 datasets, we identified two PD subtypes and explored potential biological pathways. Subsequently, using ClusterWGCNA, we pinpointed pertinent genes and developed clinical diagnostic models. We then optimized the chosen model and evaluated its association with immune infiltration. Validation was conducted using the GSE20163 dataset. Screening the single-cell dataset GSE132758 revealed cell populations associated with the identified gene. ResultsOur findings identified XGB as the optimal diagnostic model, with CAP2 identified as a pivotal gene. The risk model effectively predicted overall diagnosis rates, demonstrating a robust correlation between infiltrating immune cells and genes related to the XGB model. DiscussionIn conclusions, we identified PD subtypes and diagnostic genes associated with NETs, highlighting CAP2 as a pivotal gene. These findings have significant implications for understanding potential molecular mechanisms and treatments for PD.
“…Besides, dopamine-induced extracellular traps (ETs) are functional ( 46 ). There are two main functional regions of NETs present: the generation of oversized NETs scaffolds (consisting of whole decompressed nucDNA, histones, and various antimicrobial proteins and enzymes) used to trap and kill microorganisms in the initial immune response when neutrophils are stimulated; and the other, where activated platelets also act as an inducer of NETosis by providing adhesive interactions with neutrophils, which ultimately results in the immediate formation of cellular aggregates, from which the NETs are released to stimulate prothrombotic functions ( 22 ). Meanwhile, not only neutrophils but also mast cells, eosinophils, basophils, macrophages and also microglial cells as the resident immune cell of the CNS have been described to release nucDNA-containing ETs in response to various stimuli ( 47 , 48 ).…”
Section: Discussionmentioning
confidence: 99%
“…Different types of exDNA such cfDNA or NETs have been identified under various pathophysiological conditions (including hyperinflammation, tumor progression or neurodegeneration) in the brain and can contribute to disease onset and progression in various ways ( 19 – 21 ). A common denominator in the pathogenesis is the release of mtDNA and cfDNA, the latter being particularly available in NETs, whereby both parameters may serve as disease biomarker ( 22 ). At present, studies in neurodegenerative diseases, such as multiple spinal sclerosis ( 23 ) and Alzheimer’s disease ( 24 ) have been investigated in relation to NETs, as well as PD has been reported to demonstrate a link between mtDNA-induced inflammation and PD ( 25 ), while the mechanism of the association with NETs is still unknown.…”
IntroductionNeutrophil extracellular traps (NETs) constitute a crucial element of the immune system, and dysfunction in immune responses is implicated in the susceptibility and progression of Parkinson's disease (PD). Nevertheless, the mechanism connecting PD and NETs remains unclear. This study aims to uncover potential NETs-related immune biomarkers and elucidate their role in PD pathogenesis.MethodsThrough differential gene analysis of PD and NETs in GSE7621 datasets, we identified two PD subtypes and explored potential biological pathways. Subsequently, using ClusterWGCNA, we pinpointed pertinent genes and developed clinical diagnostic models. We then optimized the chosen model and evaluated its association with immune infiltration. Validation was conducted using the GSE20163 dataset. Screening the single-cell dataset GSE132758 revealed cell populations associated with the identified gene. ResultsOur findings identified XGB as the optimal diagnostic model, with CAP2 identified as a pivotal gene. The risk model effectively predicted overall diagnosis rates, demonstrating a robust correlation between infiltrating immune cells and genes related to the XGB model. DiscussionIn conclusions, we identified PD subtypes and diagnostic genes associated with NETs, highlighting CAP2 as a pivotal gene. These findings have significant implications for understanding potential molecular mechanisms and treatments for PD.
“…They possess phagocytic capabilities that enable them to clear harmful substances from the environment and trigger tissue inflammation [ 50 , 51 , 52 ]. Inflammation is originally a defensive reaction, yet its prolonged state can be harmful to the tissue [ 52 , 53 , 54 ]. Consequently, brain inflammation becomes a distinctive feature of Alzheimer’s disease [ 54 ].…”
Section: Introductionmentioning
confidence: 99%
“…Inflammation is originally a defensive reaction, yet its prolonged state can be harmful to the tissue [ 52 , 53 , 54 ]. Consequently, brain inflammation becomes a distinctive feature of Alzheimer’s disease [ 54 ]. As early events in AD’s pathophysiology unfold, including the increase in Aβ levels even before the formation of senile plaques, microglial activation has been observed [ 55 ].…”
Alzheimer’s disease is a neurodegenerative condition marked by the progressive deterioration of cognitive abilities, memory impairment, and the accumulation of abnormal proteins, specifically beta-amyloid plaques and tau tangles, within the brain. Despite extensive research efforts, Alzheimer’s disease remains without a cure, presenting a significant global healthcare challenge. Recently, there has been an increased focus on antibody-based treatments as a potentially effective method for dealing with Alzheimer’s disease. This paper offers a comprehensive overview of the current status of research on antibody-based molecules as therapies for Alzheimer’s disease. We will briefly mention their mechanisms of action, therapeutic efficacy, and safety profiles while addressing the challenges and limitations encountered during their development. We also highlight some crucial considerations in antibody-based treatment development, including patient selection criteria, dosing regimens, or safety concerns. In conclusion, antibody-based therapies present a hopeful outlook for addressing Alzheimer’s disease. While challenges remain, the accumulating evidence suggests that these therapies may offer substantial promise in ameliorating or preventing the progression of this debilitating condition, thus potentially enhancing the quality of life for the millions of individuals and families affected by Alzheimer’s disease worldwide.
“…Neuroinflammation is a multifactorial process occurring in the central nervous system (CNS) that is intimately linked to temporal and spatial regulation of gene expression mediated by noncoding RNAs (ncRNAs). ncRNAs are present at high concentrations in the CNS and show specific multidimensional expression, exerting immunomodulatory effects via direct or indirect interactions with various effector proteins or other molecules to form complex networks that regulate downstream immune response pathways ( 1 , 2 ). Next-generation sequencing has identified various ncRNAs dysregulated in CNS disorders, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) ( 3 – 5 ).…”
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