Causal relationship between immune cells and neurodegenerative diseases: a two-sample Mendelian randomisation study

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 29, 2024

Background There is increasing evidence that the types of immune cells are associated with various neurodegenerative diseases. However, it currently unclear whether these associations reflect causal relationships. Objective To elucidate relationship between and diseases, we conducted a two-sample Mendelian randomization (MR) analysis. Materials methods The exposure outcome GWAS data used in this study were obtained from an open-access database ( https://gwas.mrcieu.ac.uk/ ), employed MR analysis to assess 731 cell features four including Alzheimer’s disease (AD), Parkinson’s (PD), amyotrophic lateral sclerosis (ALS) multiple (MS). All was Multiple minimize bias obtain reliable estimates variables interest outcomes. Instrumental variable selection criteria restricted ensure accuracy effectiveness species risk Results identified potential relationships different Specifically, found 8 have AD, 1 type has PD, 6 ALS, MS. Conclusion Our study, through genetic means, demonstrates close specific ALS MS, providing useful guidance for future clinical researches.

Language: Английский

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Enhanced glycolysis-derived lactate promotes microglial activation in Parkinson’s disease via histone lactylation

npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 3, 2025

Language: Английский

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Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain

Acta Neuropathologica Communications, Journal Year: 2021, Volume and Issue: 9(1)

Published: Feb. 25, 2021

Abstract Pain is a common non-motor symptom of Parkinson’s disease (PD), with current limited knowledge its pathophysiology. Here, we show that peripheral inoculation mouse alpha-synuclein (α-Syn) pre-formed fibrils, in transgenic model PD, elicited retrograde trans-synaptic spreading α-Syn pathology (pSer129) across sensory neurons and dorsal nerve roots, reaching central pain processing regions, including the spinal horn projections anterolateral system nervous (CNS). Pathological to CNS propagation aggregates along interconnected neuronal populations within afferents, was concomitant impaired nociceptive response, reflected by mechanical allodynia, reduced conduction velocities (sensory motor) degeneration small- medium-sized myelinated fibers. Our findings link between transneuronal neuron dysfunction neuropathic impairment, suggesting promising avenues investigation into mechanisms underlying PD.

Language: Английский

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The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson’s disease via the microglial NLRP3 inflammasome

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: June 6, 2022

Circadian disturbance is a common nonmotor complaint in Parkinson's disease (PD). The molecular basis underlying circadian rhythm PD poorly understood. Neuroinflammation has been identified as key contributor to pathology. In this study, we explored the potential link between core clock molecule Rev-erbα and microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome pathogenesis.We first examined diurnal rhythms changes inflammatory cytokines expression SN of MPTP-induced mice. Further, used BV2 cell investigate impacts on NLRP3 microglial polarization induced by 1-methyl-4-phenylpyridinium (MPP+) αsyn pre-formed fibril. role regulating activation via NF-κB pathway was then explored. Effects SR9009 against activation, microgliosis nigrostriatal dopaminergic degeneration striatum mice were studied detail.BV2 cell-based experiments revealed through pathways. oscillation gene substantia nigra (SN) disappeared mice, well morphology. significantly elevated. Furthermore, neurons loss system partially reversed SR9009, selective agonist. addition, effectively reduced glial system.These observations suggest that protein plays an essential attenuating neuroinflammation pathology, provides therapeutic target for treatment.

Language: Английский

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Update on CSF Biomarkers in Parkinson’s Disease

Biomolecules, Journal Year: 2022, Volume and Issue: 12(2), P. 329 - 329

Published: Feb. 18, 2022

Progress in developing disease-modifying therapies Parkinson's disease (PD) can only be achieved through reliable objective markers that help to identify subjects at risk. This includes an early and accurate diagnosis as well continuous monitoring of progression therapy response. Although PD still relies mainly on clinical features, encouragingly, advances biomarker discovery have been made. The cerebrospinal fluid (CSF) is a biofluid particular interest study biomarkers since it closest the brain structures therefore could serve ideal source reflect ongoing pathologic processes. According key pathophysiological mechanisms, CSF status α-synuclein species, amyloid tau pathology, neurofilament light chain, lysosomal enzymes neuroinflammation provide promising preliminary results candidate biomarkers. Untargeted approaches field metabolomics insights into novel interconnected biological pathways. Markers based genetic forms contribute identifying subgroups suitable for gene-targeted treatment strategies might also transferable sporadic PD. Further validation analyses large cohort studies will or combinations with best value research purposes.

Language: Английский

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Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop

Current Neurology and Neuroscience Reports, Journal Year: 2022, Volume and Issue: 22(8), P. 427 - 440

Published: June 8, 2022

Abstract Purpose of Review Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps the neurodegenerative process justify growing interest anti-inflammatory agents potential disease-modifying treatments PD. The discovery inherited gene mutations PD has allowed researchers develop cellular animal models study underlying biology, but original cause neuroinflammation is still debated date. Recent Findings Cell autonomous alterations neuronal cells, including damage protein aggregation, could play role, recent findings also highlighted importance intercellular communication both local systemic level. This given rise debate about non-neuronal cells reignited intense research into gut-brain axis other interactions development disease. Whatever trigger PD, what appears quite clear that aberrant activation glial components system creates vicious circle which neurodegeneration nourish each other. Summary review, we will provide an up-to-date summary main those induced by environmental factors (e.g. gut microbiome) genetic background affected patients. Starting from lesson provided familial forms discuss pathophysiological linked inflammation idiopathic forms. Finally, comment on clinical translatability immunobiomarkers identified patient cohorts update current therapeutic strategies aimed overcoming or preventing

Language: Английский

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Blood and Cerebrospinal Fluid Biomarkers of Inflammation in Parkinson’s Disease

Journal of Parkinson s Disease, Journal Year: 2022, Volume and Issue: 12(s1), P. S183 - S200

Published: June 3, 2022

Given the clear role of inflammation in pathogenesis Parkinson's disease (PD) and its impact on incidence phenotypical characteristics, this review provides an overview with focus inflammatory biofluid markers blood cerebrospinal fluid (CSF) PD patient cohorts. In preparation for clinical trials targeting immune system, we specifically address following questions: 1) What evidence do have pro-inflammatory profiles CSF sporadic genetic patients? 2) Is there a anti-inflammatory mediators blood/CSF? 3) Do reflect those indicative cross-talk between periphery brain? 4) blood/CSF change over course as assessed repeatedly taken biosamples? 5) Are associated trajectories PD? 6) levels neurodegenerative/PD-specific biomarkers? Knowledge these questions will inform future strategies stratification cohort enrichment well suitable outcome measures trials.

Language: Английский

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Microglia and astrocyte activation is region‐dependent in the α‐synuclein mouse model of Parkinson's disease

Glia, Journal Year: 2022, Volume and Issue: 71(3), P. 571 - 587

Published: Nov. 10, 2022

Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated the basal inflammatory tone differed between brain regions and, consequently, reaction generated pro-inflammatory stimulus was different. In this study, assessed innate immune midbrain and striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing α-synuclein mCherry genes or gene administered into substantia nigra. Myeloid cells (CD11b+ ) astrocytes (ACSA2+ were purified from for bulk RNA sequencing. parkinsonian midbrain, CD11b+ presented unique anti-inflammatory transcriptomic profile degenerative microglia signatures described models other conditions. By contrast, striatal showed state similar disease-associated microglia. prominent increase infiltrated monocytes/macrophages observed together with microglia, participated actively phagocytosis dopaminergic bodies. Although phagocytic profile, morphology cell density preserved no active detected. Interestingly, fingerprint low number differentially displayed transcripts striatum. During α-synuclein-dependent degeneration, experience context-dependent activation states different contribution reaction. Our results point towards relevance selecting appropriate targets design neuroprotective strategies aimed modulate system during phase degeneration.

Language: Английский

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Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson’s disease and cognition

Brain Behavior and Immunity, Journal Year: 2022, Volume and Issue: 101, P. 182 - 193

Published: Jan. 10, 2022

Alpha-synuclein pathology is associated with immune activation and neurodegeneration in Parkinson's disease. The involves not only microglia but also peripheral cells, such as mononuclear phagocytes found blood infiltrated the brain. Understanding involvement essential for developing immunomodulatory treatment. Therefore, we aimed to study circulating early- late-stage disease, defined by disease duration of less or more than five years, respectively, analyze their association clinical phenotypes. We performed a cross-sectional multi-color flow cytometry on 78 sex-balanced individuals sporadic 28 controls, longitudinal samples from seven patients one control. Cell frequencies surface marker expressions natural killer monocyte subtypes, dendritic cells were compared between groups correlated standardized scores. elevated levels migration- (CCR2, CD11b) phagocytic- (CD163) markers, particularly classical intermediate monocytes early HLA-DR expression was increased advanced stages whereas TLR4 decreased women Disease. disease-associated changes CCR2 CD11b worse cognition. Increased TLR2 related motor symptoms. In conclusion, our data highlights relevance symptomatic presentation role CD163+ migration-competent cognitive defects. Our suggests that system dynamically altered directly both symptoms sex bias

Language: Английский

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The Endotoxin Hypothesis of Parkinson's Disease

Movement Disorders, Journal Year: 2023, Volume and Issue: 38(7), P. 1143 - 1155

Published: May 8, 2023

The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to pathogenesis this disorder. LPS are found in, and released from, outer membrane Gram-negative bacteria, for example in gut. It proposed gut dysfunction early PD leads elevated levels wall blood, which promotes both α-synuclein aggregation enteric neurons a peripheral inflammatory response. Communication brain via circulating cytokines blood and/or gut-brain axis neuroinflammation spreading pathology, exacerbating neurodegeneration brainstem nuclei loss dopaminergic substantia nigra, manifesting clinical symptoms PD. evidence supporting includes: (1) dysfunction, permeability, bacterial changes occur PD, (2) serum increased proportion patients, (3) induces expression, aggregation, neurotoxicity, (4) causes activation monocytes leading cytokine production, (5) inflammation specific midbrain neurons, mediated by microglia. If correct, then treatment options might include: changing microbiome, reducing levels, or blocking response immune cells microglia LPS. However, has number limitations requires further testing, particular whether can reduce incidence, progression, severity. © 2023 Authors. Movement Disorders published Wiley Periodicals LLC on behalf International Parkinson Disorder Society.

Language: Английский

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