Association of peripheral immune activation with amyotrophic lateral sclerosis and Parkinson's disease: A systematic review and meta-analysis.

BACKGROUND: Recent studies have revealed the link between immune activation and neurodegenerative diseases. METHODS: By employing meta-analysis, we estimated the standardized mean difference (SMD) and their corresponding 95% confidence intervals (CIs) between the groups. RESULTS: According to the pre-set criteria, a total of 21 published articles including 2377 ALS patients and 1244 HCs, as well as 60 articles including 5111 PD patients and 4237 HCs, were identified. This study provided evidence of peripheral immune activation in the pathogenesis of ALS and PD. CONCLUSION: Our results suggested monitoring changes in peripheral blood immune cell populations, particularly lymphocyte subsets, will benefit understanding the developments and exploring reliable and specific biomarkers of these two diseases.

Binding Stability of Antibody-α-Synuclein Complexes Predicts the Protective Efficacy of Anti-α-synuclein Antibodies.

Spreading of alpha-synuclein (αSyn) may play an important role in Parkinson's disease and related synucleinopathies. Passive immunization with anti-αSyn antibodies is a promising method to slow down the spreading process and thereby the progression of synucleinopathies. Currently, it remains elusive which specific characteristics are essential to render therapeutic antibodies efficacious. Here, we established a neuronal co-culture model, in which αSyn species are being released from αSyn-overexpressing cells and induce toxicity in a priori healthy GFP-expressing cells. In this model, we investigated the protective efficacy of three anti-αSyn antibodies. Only two of these antibodies, one C-terminal and one N-terminal, protected from αSyn-induced toxicity by inhibiting the uptake of spreading-competent αSyn from the cell culture medium. Neither the binding epitope nor the affinity of the antibodies towards recombinant αSyn could explain differences in biological efficacy. However, both protective antibodies formed more stable antibody-αSyn complexes than the non-protective antibody. These findings indicate that the stability of antibody-αSyn complexes may be more important to confer protection than the binding epitope or affinity to recombinant αSyn.

The role of Th17 cells/IL-17A in AD, PD, ALS and the strategic therapy targeting on IL-17A.

Neurodegenerative diseases are a group of disorders characterized by progressive loss of certain populations of neurons, which eventually lead to dysfunction. These diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Immune pathway dysregulation is one of the common features of neurodegeneration. Recently, there is growing interest in the specific role of T helper Th 17 cells and Interleukin-17A (IL-17A), the most important cytokine of Th 17 cells, in the pathogenesis of the central nervous system (CNS) of neurodegenerative diseases. In the present study, we summarized current knowledge about the function of Th17/IL-17A, the physiology of Th17/IL-17A in diseases, and the contribution of Th17/IL-17A in AD, PD, and ALS. We also update the findings on IL-17A-targeting drugs as potentially immunomodulatory therapeutic agents for neurodegenerative diseases. Although the specific mechanism of Th17/IL-17A in this group of diseases is still controversial, uncovering the molecular pathways of Th17/IL-17A in neurodegeneration allows the identification of suitable targets to modulate these cellular processes. Therapeutics targeting IL-17A might represent potentially novel anti-neurodegeneration drugs.

LRRK2 as a target for modulating immune system responses.

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are associated with familial and sporadic cases of Parkinson's disease (PD) but are also found in patients with immune- related disorders, such as inflammatory bowel disease (IBD) and leprosy, linking LRRK2 to the immune system. Supporting this genetic evidence, in the last decade LRRK2 was robustly shown to modulate inflammatory responses at both systemic and central nervous system level. In this review, we recapitulate the role of LRRK2 in central and peripheral inflammation in PD and inflammatory disease models. Moreover, we discuss how LRRK2 inhibitors and anti- inflammatory drugs may be beneficial at reducing disease risk/progression in LRRK2-mutation carriers and manifesting PD patients, thus supporting LRRK2 as a promising disease-modifying PD strategy.

Fat and Protein Combat Triggers Immunological Weapons of Innate and Adaptive Immune Systems to Launch Neuroinflammation in Parkinson's Disease.

Parkinson's disease (PD) is the second-most common neurodegenerative disease in the world, affecting up to 10 million people. This disease mainly happens due to the loss of dopaminergic neurons accountable for memory and motor function. Partial glucocerebrosidase enzyme deficiency and the resultant excess accumulation of glycosphingolipids and alpha-synuclein (α-syn) aggregation have been linked to predominant risk factors that lead to neurodegeneration and memory and motor defects in PD, with known and unknown causes. An increasing body of evidence uncovers the role of several other lipids and their association with α-syn aggregation, which activates the innate and adaptive immune system and sparks brain inflammation in PD. Here, we review the emerging role of a number of lipids, i.e., triglyceride (TG), diglycerides (DG), glycerophosphoethanolamines (GPE), polyunsaturated fatty acids (PUFA), sphingolipids, gangliosides, glycerophospholipids (GPL), and cholesterols, and their connection with α-syn aggregation as well as the induction of innate and adaptive immune reactions that trigger neuroinflammation in PD.

The neuroinflammatory role of glucocerebrosidase in Parkinson's disease.

The lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene, is a membrane-associated protein catalyzing the cleavage of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Homologous GBA1 mutations cause Gaucher disease (GD) and heterologous mutations cause Parkinson's disease (PD). Importantly, heterologous GBA1 mutations are recognized as the second risk factor of PD. The pathological features of PD are Lewy neurites (LNs) and Lewy bodies (LBs) composed of pathological α-synuclein. Oxidative stress, inflammatory response, autophagic impairment, and α-synuclein accumulation play critical roles in PD pathogenic cascades, but the pathogenesis of PD has not yet been fully elucidated. What's more, PD treatment drugs can only relieve symptoms to a certain extent, but cannot alleviate neurodegenerative progression. Therefore, it's urgent to explore new targets that can alleviate the neurodegenerative process. Deficient GCase can cause lysosomal dysfunction, obstructing the metabolism of α-synuclein. Meanwhile, GCase dysfunction causes accumulation of its substrates, leading to lipid metabolism disorders. Subsequently, astrocytes and microglia are activated, releasing amounts of pro-inflammatory mediators and causing extensive neuroinflammation. All these cascades can induce neuron damage and death, eventually promoting PD pathology. This review aims to summarize these points and the potential of GCase as an original target to provide some ideas for elucidating the pathogenesis of PD.

Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease: A Cross-sectional Study.

BACKGROUND AND OBJECTIVES: There has been growing interest in potential roles of the immune system in the pathogenesis of Parkinson disease (PD). The aim of the current study was to comprehensively characterize phenotypic and functional profiles of circulating immune cells in patients with PD vs controls. METHODS: Peripheral blood was collected from patients with PD and age- and sex-matched neurologically normal controls (NCs) in 2 independent cohorts (discovery and validation). Comprehensive multicolor flow cytometry was performed on whole blood leukocytes and peripheral blood mononuclear cells to characterize different immune subsets and their ex vivo responses. RESULTS: The discovery cohort included 17 NCs and 12 participants with PD, and the validation cohort included 18 NCs and 18 participants with PD. Among major immune cell types, B cells appeared to be preferentially affected in PD. Proliferating B cell counts were decreased in patients with PD compared with controls. Proportions of B-cell subsets with regulatory capacity such as transitional B cells were preferentially reduced in the patients with PD, whereas proportions of proinflammatory cytokine-producing B cells increased, resulting in a proinflammatory shift of their B-cell functional cytokine responses. Unsupervised principal component analysis revealed increased expression of TNFα and GM-CSF by both B cells and T cells of patients with PD. In addition, levels of follicular T cells, an important B-cell helper T-cell population, decreased in the patients with PD, correlating with their B-cell abnormality. DISCUSSION: Our findings define a novel signature of peripheral immune cells and implicate aberrant Tfh:B-cell interactions in patients with PD.

Targeting alpha-synuclein via the immune system in Parkinson's disease: Current vaccine therapies.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD.

GCH1 Deficiency Activates Brain Innate Immune Response and Impairs Tyrosine Hydroxylase Homeostasis.

The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant (gch1-/-), using CRISPR/Cas technology. gch1-/- zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gch1-/- larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1-/- larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gch1-/- The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.SIGNIFICANCE STATEMENT Genome-wide association studies have now identified at least 90 genetic risk factors for sporadic Parkinson's disease (PD). Zebrafish are an ideal tool to determine the mechanistic role of genome-wide association studies (GWAS) risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase 1 (GCH1) as a genetic risk factor for PD was counterintuitive, GCH1 is the rate-limiting enzyme in the synthesis of dopamine (DA), mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing DAergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase (Th) homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.

Potential Role of Akkermansia muciniphila in Parkinson's Disease and Other Neurological/Autoimmune Diseases.

The composition of the gut microbiota, including Akkermansia muciniphila (A. muciniphila), is altered in many neurological diseases and may be involved in the pathophysiological processes of Parkinson's disease (PD). A. muciniphila, a mucin-degrading bacterium, is a potential next-generation microbe that has anti-inflammatory properties and is responsible for keeping the body healthy. As the role of A. muciniphila in PD has become increasingly apparent, we discuss the potential link between A. muciniphila and various neurological diseases (including PD) in the current review.

Neuro-Immunity and Gut Dysbiosis Drive Parkinson's Disease-Induced Pain.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1-2% of the population aged 65 and over. Additionally, non-motor symptoms such as pain and gastrointestinal dysregulation are also common in PD. These impairments might stem from a dysregulation within the gut-brain axis that alters immunity and the inflammatory state and subsequently drives neurodegeneration. There is increasing evidence linking gut dysbiosis to the severity of PD's motor symptoms as well as to somatosensory hypersensitivities. Altogether, these interdependent features highlight the urgency of reviewing the links between the onset of PD's non-motor symptoms and gut immunity and whether such interplays drive the progression of PD. This review will shed light on maladaptive neuro-immune crosstalk in the context of gut dysbiosis and will posit that such deleterious interplays lead to PD-induced pain hypersensitivity.

Reduced Immunosenescence of Peripheral Blood T Cells in Parkinson's Disease with CMV Infection Background.

Immunosenescence is a process of remodeling the immune system under the influence of chronic inflammation during aging. Parkinson's disease (PD) is a common age-associated neurodegenerative disorder and is frequently accompanied by neuroinflammation. On the other hand, cytomegalovirus (CMV), one of the most spread infections in humans, may induce chronic inflammation which contributes to immunosenescence, differentiation and the inflation of T cells and NK cells. Currently, there is no clear understanding of immunosenescence severity in PD patients infected with CMV. In this study, we analyzed differentiation stages and immunosenescence characteristics of T cells and NK cells in 31 patients with mild and moderate PD severity, 33 age-matched and 30 young healthy donors. The PD patients were 100% CMV-seropositive compared to 76% age-matched and 73% young CMV-infected healthy donors. The proportion of effector memory T cells re-expressing CD45RA, CD57+CD56- T cells and CD57+CD56+ T cells was significantly reduced in PD patients compared with CMV-seropositive age-matched healthy individuals. The CD57+CD56- T cell proportion in PD patients was similar to that of CMV-seropositive young healthy donors. Thus, PD is characterized by reduced peripheral blood T cell immunosenescence, even against the background of CMV infection.

Immunomodulation induced by central nervous system-related peptides as a therapeutic strategy for neurodegenerative disorders.

Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.

T lymphocyte senescence is attenuated in Parkinson's disease.

BACKGROUND: Immune involvement is well-described in Parkinson's disease (PD), including an adaptive T lymphocyte response. Given the increasing prevalence of Parkinson's disease in older age, age-related dysregulation of T lymphocytes may be relevant in this disorder, and we have previously observed changes in age-associated CD8+ T cell subsets in mid-stage PD. This study aimed to further characterise T cell immunosenescence in newly diagnosed PD patients, including shifts in CD4+ and CD8+ subpopulations, and changes in markers of cellular ageing in CD8+ T lymphocytes. METHODS: Peripheral blood mononuclear cells were extracted from the blood of 61 newly diagnosed PD patients and 63 age- and sex-matched controls. Flow cytometric analysis was used for immunophenotyping of CD8+ and CD4+ lymphocyte subsets, and analysis of recent thymic emigrant cells. Telomere length within CD8+ T lymphocytes was assessed, as well as the expression of the telomerase reverse transcriptase enzyme (hTERT), and the cell-ageing markers p16INK4a and p21CIP1/Waf1. RESULTS: The number of CD8+ TEMRA T cells was found to be significantly reduced in PD patients compared to controls. The expression of p16INK4a in CD8+ lymphocytes was also lower in patients versus controls. Chronic latent CMV infection was associated with increased senescent CD8+ lymphocytes in healthy controls, but this shift was less apparent in PD patients. CONCLUSIONS: Taken together, our data demonstrate a reduction in CD8+ T cell replicative senescence which is present at the earliest stages of Parkinson's disease.

Integrative analysis of potential biomarkers and immune cell infiltration in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease in the elderly population. However, there are no reliable diagnostic biomarkers for PD, and the pathogenesis of PD still needs further study. The aim of the current study was to identify potential biomarkers and explore the pathogenesis of PD. METHODS: We conducted an integrative analysis of messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) expression profiles of PD using data from the Gene Expression Omnibus (GEO). The GSE110720, GSE110719 and GSE133347 data sets were selected and analysed. Gene ontology (GO) enrichment and gene set variation analysis (GSVA) were performed for annotation, visualization, and integrated discovery. Protein-protein interaction (PPI) and competing endogenous RNA (ceRNA) networks were constructed, and hub genes were identified. Meanwhile, the immune infiltration analysis of hub genes was analysed. Moreover, receiver operating characteristic (ROC) curves were generated to verify the diagnostic value of the differentially expressed genes (DEGs). Finally, the genes with high area under the curve (AUC) values were verified by human samples. RESULTS: We identified 464 DEGs closely related to PD, including 154 mRNAs, 134 miRNAs, and 176 lncRNAs. The GO analyses indicated that changes in PD were mainly enriched in receptor ligand activity and cytokine receptor binding. The KEGG enrichment analysis showed that these DEGs were significantly involved in cytokine-cytokine receptor interactions, signalling pathways regulating the pluripotency of stem cells and Th17 cell differentiation. GSVA suggested that growth factor binding, IL2-stat5 signalling, and IL6-jak-stat3 signalling were crucial in the development of PD. A total of five hub genes (NPBWR2, CXCL10, CXCL5, S1PR5, and GALR1) were selected via the PPI network. A ceRNA network of the CXCL5, CXCL10 and S1PR5 genes was constructed, and target genes of the three genes were screened. The immune infiltration analysis showed that there were significant differences in a variety of immune cells between the hub genes. The expression of DEGs was validated in clinical human samples by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression levels of hsa-miR6895-5p, hsa-miR6791-5p, hsa-miR518f-5p, hsa-miR455-3p and TEKT4P2 were decreased, while the levels of TPTE2P6 were increased in human samples. These findings are consistent with the bioinformatics analysis results. CONCLUSION: We found that the immune inflammatory response and immune cell regulation were involved in the pathogenesis of PD. Five hub genes involved in the immune infiltration biological processes of PD based on bioinformatics. We verified the DEGs with significant differences by qRT-PCR. These findings might provide new insight into the pathogenesis of PD and the development of diagnostic and therapeutic strategies for PD.

Drosophila as a Model for Microbiota Studies of Neurodegeneration.

Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly's gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior.

Flavin-containing monooxygenase 1 deficiency promotes neuroinflammation in dopaminergic neurons in mice.

A growing body of evidence indicates an association between flavin-containing monooxygenase (FMO) and neurodegeneration, including Parkinson's disease (PD); however, the details of this association are unclear. We previously showed that the level of Fmo1 mRNA is decreased in an in vitro rotenone model of parkinsonism. To further explore the potential involvement of FMO1 deficiency in parkinsonism, we generated Fmo1 knockout (KO) mice and examined the survival of dopaminergic neurons and relative changes. Fmo1 KO mice exhibited loss of tyrosine hydroxylase-positive neurons, decreased levels of tyrosine hydroxylase and Parkin proteins, and increased levels of pro-inflammatory cytokines (IL1ß and IL6) in the nigrostriatal region. Moreover, the protein levels of PTEN induced kinase 1 (PINK1) and p62, and the Microtubule associated protein 1 light chain 3 (LC3)-II/I ratio were not significantly altered in Fmo1 KO mice (P > 0.05). FMO1 deficiency promotes neuroinflammation in dopaminergic neurons in mice, thus may plays a potential pathological role in dopaminergic neuronal loss. These findings may provide new insight into the pathogenesis of PD.

Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology.

BACKGROUND: The etiology of sporadic Parkinson's disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. METHODS: We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)-an inhibitor of nuclear factor kappa B (NFκB)-to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. RESULTS: High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. CONCLUSIONS: This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice.

Highlighting Immune System and Stress in Major Depressive Disorder, Parkinson's, and Alzheimer's Diseases, with a Connection with Serotonin.

There is recognition that both stress and immune responses are important factors in a variety of neurological disorders. Moreover, there is an important role of several neurotransmitters that connect these factors to several neurological diseases, with a special focus in this paper on serotonin. Accordingly, it is known that imbalances in stressors can promote a variety of neuropsychiatric or neurodegenerative pathologies. Here, we discuss some facts that link major depressive disorder, Alzheimer's, and Parkinson's to the stress and immune responses, as well as the connection between these responses and serotonergic signaling. These are important topics of investigation which may lead to new or better treatments, improving the life quality of patients that suffer from these conditions.

Nilotinib inhibits microglia-mediated neuroinflammation to protect against dopaminergic neuronal death in Parkinson's disease models.

Microglia-mediated neuroinflammation is tightly correlated with the etiology and progression of neurodegenerative disorders, including Parkinson's disease (PD). Nilotinib, a c-Abl inhibitor used for chronic myeloid leukemia, has been proven effective in relieving PD progression. However, whether nilotinib could affect neuroinflammation is largely unknown. In this current study, we investigated the role of nilotinib in microglia-mediated neuroinflammatory response in Parkinson's disease. Lipopolysaccharide (LPS)-induced neuroinflammation in BV2 microglial cells and mouse brains were used as models for Parkinson's disease. Our results demonstrated that nilotinib significantly suppressed LPS-induced neuroinflammation by reducing the production of pro-inflammatory factors including iNOS, COX-2, IL-1ß, IL-6 and TNF-α in BV2 cells. Moreover, pretreatment of nilotinib attenuated the neurotoxicity of LPS-treated microglial conditioned medium to MES23.5 dopaminergic (DA) neurons. Mechanismly, nilotinib inhibited NF-κB signaling pathway and suppressed the nuclear translocation of p65 upon LPS stimulation. In LPS-injected mouse brains, nilotinib administration markedly suppressed the activation of microglia and down-regulated COX-2 as well as IL-1ß expression. Most importantly, nilotinib effectively protected against microglial activation-mediated mouse DA neuronal loss. Taken together, our study suggests that nilotinib exerts anti-neuroinflammatory effect and protects DA neurons from activated microglia-induced inflammatory damage through suppressing NF-κB signaling pathway, indicating its potential application in further clinical trials.