Journal of Neuroinflammation最新文献

{"title":"Alterations of the IKZF1-IKZF2 tandem in immune cells of schizophrenia patients regulate associated phenotypes.","authors":"Iván Ballasch, Laura López-Molina, Marcos Galán-Ganga, Anna Sancho-Balsells, Irene Rodríguez-Navarro, Sara Borràs-Pernas, M Angeles Rabadan, Wanqi Chen, Carlota Pastó-Pellicer, Francesca Flotta, Wang Maoyu, Joaquín Fernández-Irigoyen, Enrique Santamaría, Ruth Aguilar, Carlota Dobaño, Natalia Egri, Carla Hernandez, Miqueu Alfonso, Manel Juan, Jordi Alberch, Daniel Del Toro, Belén Arranz, Josep M Canals, Albert Giralt","doi":"10.1186/s12974-024-03320-3","DOIUrl":"https://doi.org/10.1186/s12974-024-03320-3","url":null,"abstract":"<p><p>Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients' peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenia-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 mRNA levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenia-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"326"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tension at the gate: sensing mechanical forces at the blood-brain barrier in health and disease.","authors":"Cathrin E Hansen, David Hollaus, Alwin Kamermans, Helga E de Vries","doi":"10.1186/s12974-024-03321-2","DOIUrl":"https://doi.org/10.1186/s12974-024-03321-2","url":null,"abstract":"<p><p>Microvascular brain endothelial cells tightly limit the entry of blood components and peripheral cells into the brain by forming the blood-brain barrier (BBB). The BBB is regulated by a cascade of mechanical and chemical signals including shear stress and elasticity of the adjacent endothelial basement membrane (BM). During physiological aging, but especially in neurological diseases including multiple sclerosis (MS), stroke, small vessel disease, and Alzheimer's disease (AD), the BBB is exposed to inflammation, rigidity changes of the BM, and disturbed cerebral blood flow (CBF). These altered forces lead to increased vascular permeability, reduced endothelial reactivity to vasoactive mediators, and promote leukocyte transmigration. Whereas the molecular players involved in leukocyte infiltration have been described in detail, the importance of mechanical signalling throughout this process has only recently been recognized. Here, we review relevant features of mechanical forces acting on the BBB under healthy and pathological conditions, as well as the endothelial mechanosensory elements detecting and responding to altered forces. We demonstrate the underlying complexity by focussing on the family of transient receptor potential (TRP) ion channels. A better understanding of these processes will provide insights into the pathogenesis of several neurological disorders and new potential leads for treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"325"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dorsoventral photobiomodulation therapy safely reduces inflammation and sensorimotor deficits in a mouse model of multiple sclerosis.","authors":"Vincent Escarrat, Davide Reato, Guillaume Blivet, Jacques Touchon, Geneviève Rougon, Rémi Bos, Franck Debarbieux","doi":"10.1186/s12974-024-03294-2","DOIUrl":"https://doi.org/10.1186/s12974-024-03294-2","url":null,"abstract":"<p><strong>Background: </strong>Non-invasive photobiomodulation therapy (PBMT), employing specific infrared light wavelengths to stimulate biological tissues, has recently gained attention for its application to treat neurological disorders. Here, we aimed to uncover the cellular targets of PBMT and assess its potential as a therapeutic intervention for multiple sclerosis (MS).</p><p><strong>Methods: </strong>We applied daily dorsoventral PBMT in an experimental autoimmune encephalomyelitis (EAE) mouse model, which recapitulates key features of MS, and revealed a strong positive impact of PBMT on the sensorimotor deficits. To understand the cellular mechanisms underlying these striking effects, we used state-of-the-art tools and methods ranging from two-photon longitudinal imaging of triple fluorescent reporter mice to histological investigations and patch-clamp electrophysiological recordings.</p><p><strong>Results: </strong>We found that PBMT induced anti-inflammatory and neuroprotective effects in the dorsal spinal cord. PBMT prevented peripheral immune cell infiltration, glial reactivity, as well as the EAE-induced hyperexcitability of spinal interneurons, both in dorsal and ventral areas, which likely underlies the behavioral effects of the treatment. Thus, aside from confirming the safety of PBMT in healthy mice, our preclinical investigation suggests that PBMT exerts a systemic and beneficial effect on the physiopathology of EAE, primarily resulting in the modulation of the inflammatory processes.</p><p><strong>Conclusion: </strong>PBMT may therefore represent a new valuable therapeutic option to treat MS symptoms.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"321"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral immune cell dysregulation following diffuse traumatic brain injury in pigs.","authors":"Kathryn L Wofford, Kevin D Browne, David J Loane, David F Meaney, D Kacy Cullen","doi":"10.1186/s12974-024-03317-y","DOIUrl":"https://doi.org/10.1186/s12974-024-03317-y","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a global health problem affecting millions of individuals annually, potentially resulting in persistent neuropathology, chronic neurological deficits, and death. However, TBI not only affects neural tissue, but also affects the peripheral immune system's homeostasis and physiology. TBI disrupts the balanced signaling between the brain and the peripheral organs, resulting in immunodysregulation and increasing infection susceptibility. Indeed, secondary infections following TBI worsen neurological outcomes and are a major source of mortality and morbidity. Despite the compelling link between the damaged brain and peripheral immune functionality, little is known about how injury severity affects the peripheral immune system in closed-head diffuse TBI, the most common clinical presentation including all concussions. Therefore, we characterized peripheral blood mononuclear cells (PBMCs) and plasma changes over time and across injury severity using an established large-animal TBI model of closed-head, non-impact diffuse rotational acceleration in pigs. Across all timepoints and injury levels, we did not detect any changes to plasma cytokine concentrations. However, changes to the PBMCs were detectable and much more robust. We observed the concentration and physiology of circulating PBMCs changed in an injury severity-dependent manner, with most cellular changes occurring within the first 10 days following a high rotational velocity injury. Here, we report changes in the concentrations of myeloid and T cells, changes in PBMC composition, and changes in phagocytic clearance over time. Together, these data suggest that following a diffuse brain injury in a clinically relevant large-animal TBI model, the immune system exhibits perturbations that are detectable into the subacute timeframe. These findings invite future investigations into therapeutic interventions targeting peripheral immunity and the potential for peripheral blood cellular characterization as a diagnostic tool.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"324"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of noradrenergic inhibition on neuroinflammation and pathophysiology in mouse models of Alzheimer's disease.","authors":"Andrew K Evans, Heui Hye Park, Claire E Woods, Rachel K Lam, Daniel Ryskamp Rijsketic, Christine Xu, Emily K Chu, Peter Ciari, Sarah Blumenfeld, Laura M Vidano, Nay Lui Saw, Boris D Heifets, Mehrdad Shamloo","doi":"10.1186/s12974-024-03306-1","DOIUrl":"https://doi.org/10.1186/s12974-024-03306-1","url":null,"abstract":"<p><p>Norepinephrine (NE) modulates cognitive function, arousal, attention, and responses to novelty and stress, and it also regulates neuroinflammation. We previously demonstrated behavioral and immunomodulatory effects of beta-adrenergic pharmacology in mouse models of Alzheimer's disease (AD). The current studies were designed to block noradrenergic signaling in 5XFAD mice through (1) chemogenetic inhibition of the locus coeruleus (LC), (2) pharmacologic blocking of β-adrenergic receptors, and (3) conditional deletion of β1- or β2-adrenergic receptors (adrb1 or adrb2) in microglia.First, brain-wide AD pathology was mapped in 3D by imaging immunolabeled, cleared 5XFAD brains to assess the overlap between amyloid beta (Aβ) pathology, reactive microglia, and the loss of tyrosine hydroxylase (TH) expression in the catecholaminergic system. To examine the effects of inhibiting the LC NE system in the 5XFAD model, inhibitory (Gi) DREADD receptors were expressed specifically in LC NE neurons. LC NE neurons were chronically inhibited through the subcutaneous pump administration of the DREADD agonist clozapine-N-oxide (CNO). Plasma and brains were collected for assessment of neuroinflammation and pathology. A separate cohort of 5XFAD mice was chronically dosed with the beta-adrenergic antagonist propranolol or vehicle and evaluated for behavior, as well as post-mortem neuroinflammation and pathology. Finally, we used 5XFAD mice with conditional deletion of either adrb1 or adrb2 in microglia to assess neuroinflammation and pathology mediated by β-adrenergic signaling.Using iDISCO+, light sheet fluorescence microscopy, and novel analyses, we detected widespread microgliosis and Aβ pathology, along with modest TH downregulation in fibers across multiple brain regions, in contrast to the spatially limited TH downregulation observed in neurons. Both chemogenetic inhibition of LC adrenergic signaling and pharmacological inhibition of beta-adrenergic receptors potentiated neuroinflammation without altering Aβ pathology. Conditional deletion of adrb1 in microglia did not affect neuroinflammation. Conditional deletion of adrb2 in microglia attenuated inflammation and pathology in females but had no effect in males. Overall, these data support previous observations demonstrating the immunomodulatory effects of beta-adrenergic signaling in the pathophysiology of brain disorders and suggest that adrenergic receptors on cell types other than microglia, such as astrocytes, may mediate some of the disease-modifying effects of β-adrenergic agonists in the brain.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"322"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia in the aged brain develop a hypoactive molecular phenotype after surgery.","authors":"Zhuoran Yin, Anna K Leonard, Carl M Porto, Zhongcong Xie, Sebastian Silveira, Deborah J Culley, Oleg Butovsky, Gregory Crosby","doi":"10.1186/s12974-024-03307-0","DOIUrl":"https://doi.org/10.1186/s12974-024-03307-0","url":null,"abstract":"<p><strong>Background: </strong>Microglia, the resident immune cells of the brain, play a crucial role in maintaining homeostasis in the central nervous system (CNS). However, they can also contribute to neurodegeneration through their pro-inflammatory properties and phagocytic functions. Acute post-operative cognitive deficits have been associated with inflammation, and microglia have been implicated primarily based on morphological changes. We investigated the impact of surgery on the microglial transcriptome to test the hypothesis that surgery produces an age-dependent pro-inflammatory phenotype in these cells.</p><p><strong>Methods: </strong>Three-to-five and 20-to-22-month-old C57BL/6 mice were anesthetized with isoflurane for an abdominal laparotomy, followed by sacrifice either 6 or 48 h post-surgery. Age-matched controls were exposed to carrier gas. Cytokine concentrations in plasma and brain tissue were evaluated using enzyme-linked immunosorbent assays (ELISA). Iba1⁺ cell density and morphology were determined by immunohistochemistry. Microglia from both surgically treated mice and age-matched controls were isolated by a well-established fluorescence-activated cell sorting (FACS) protocol. The microglial transcriptome was then analyzed using quantitative polymerase chain reaction (qPCR) and RNA sequencing (RNAseq).</p><p><strong>Results: </strong>Surgery induced an elevation in plasma cytokines in both age groups. Notably, increased CCL2 was observed in the brain post-surgery, with a greater change in old compared to young mice. Age, rather than the surgical procedure, increased Iba1 immunoreactivity and the number of Iba1⁺ cells in the hippocampus. Both qPCR and RNAseq analysis demonstrated suppression of neuroinflammation at 6 h after surgery in microglia isolated from aged mice. A comparative analysis of differentially expressed genes (DEGs) with previously published neurodegenerative microglia phenotype (MGnD), also referred to disease-associated microglia (DAM), revealed that surgery upregulates genes typically downregulated in the context of neurodegenerative diseases. These surgery-induced changes resolved by 48 h post-surgery and only a few DEGs were detected at that time point, indicating that the hypoactive phenotype of microglia is transient.</p><p><strong>Conclusions: </strong>While anesthesia and surgery induce pro-inflammatory changes in the plasma and brain of mice, microglia adopt a homeostatic molecular phenotype following surgery. This effect seems to be more pronounced in aged mice and is transient. These results challenge the prevailing assumption that surgery activates microglia in the aged brain.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"323"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyro3 and Gas6 are associated with white matter and myelin integrity in multiple sclerosis.","authors":"Igal Rosenstein, Lenka Novakova, Hlin Kvartsberg, Anna Nordin, Sofia Rasch, Elzbieta Rembeza, Sofia Sandgren, Clas Malmeström, Stefanie Fruhwürth, Markus Axelsson, Kaj Blennow, Henrik Zetterberg, Jan Lycke","doi":"10.1186/s12974-024-03315-0","DOIUrl":"10.1186/s12974-024-03315-0","url":null,"abstract":"<p><strong>Background: </strong>The Gas6/TAM (Tyro3, Axl, and Mer) receptor system has been implicated in demyelination and delayed remyelination in experimental animal models, but data in humans are scarce. We aimed to investigate the role of Gas6/TAM in neurodegenerative processes in multiple sclerosis (MS).</p><p><strong>Methods: </strong>From a prospective 5-year follow-up study, soluble Gas6/TAM biomarkers were analyzed in cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA) at baseline in patients with relapsing-remitting MS (RRMS) (n = 40), progressive MS (PMS) (n = 20), and healthy controls (HC) (n = 25). Brain volumes, including myelin content (MyC) and white matter (WM) were measured by synthetic magnetic resonance imaging at baseline, 12 months, and 60-month follow-up. Associations with brain volume changes were investigated in multivariable linear regression models. Gas6/TAM concentrations were also determined at 12 months follow-up in RRMS to assess treatment response.</p><p><strong>Results: </strong>Baseline concentrations of Tyro3, Axl, and Gas6 were significantly higher in PMS vs. RRMS and HC. Mer was higher in PMS vs. HC. Tyro3 and Gas6 were associated with reduced WM (β = 25.5, 95% confidence interval [CI] [6.11-44.96, p = 0.012; β = 11.4, 95% CI [0.42-22.4], p = 0.042, respectively) and MyC (β = 7.95, 95%CI [1.84-14.07], p = 0.012; β = 4.4, 95%CI [1.04-7.75], p = 0.012 respectively) at 60 months. Patients with evidence of remyelination at last follow-up had lower baseline soluble Tyro3 (p = 0.033) and Gas6 (p = 0.014). Except Mer, Gas6/TAM concentrations did not change with treatment in RRMS.</p><p><strong>Discussion: </strong>Our data indicate a potential role for the Gas6/TAM receptor system in neurodegenerative processes influencing demyelination and ineffective remyelination.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"320"},"PeriodicalIF":9.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glyphosate exposure exacerbates neuroinflammation and Alzheimer's disease-like pathology despite a 6-month recovery period in mice.","authors":"Samantha K Bartholomew, Wendy Winslow, Ritin Sharma, Khyatiben V Pathak, Savannah Tallino, Jessica M Judd, Hector Leon, Julie Turk, Patrick Pirrotte, Ramon Velazquez","doi":"10.1186/s12974-024-03290-6","DOIUrl":"10.1186/s12974-024-03290-6","url":null,"abstract":"<p><strong>Background: </strong>Glyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that C57BL/6J mice dosed with glyphosate for 14 days showed glyphosate and its major metabolite aminomethylphosphonic acid present in brain tissue, with corresponding increases in pro-inflammatory cytokine tumor necrosis factor-⍺ (TNF-⍺) in the brain and peripheral blood plasma. Since TNF-⍺ is elevated in neurodegenerative disorders such as Alzheimer's Disease (AD), in this study, we asked whether glyphosate exposure serves as an accelerant of AD pathogenesis. Additionally, whether glyphosate and aminomethylphosphonic acid remain in the brain after a recovery period has yet to be examined.</p><p><strong>Methods: </strong>We hypothesized that glyphosate exposure would induce neuroinflammation in control mice, while exacerbating neuroinflammation in AD mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. We dosed 4.5-month-old 3xTg-AD and non-transgenic (NonTg) control mice with either 0, 50 or 500 mg/kg of glyphosate daily for 13 weeks followed by a 6-month recovery period.</p><p><strong>Results: </strong>We found that aminomethylphosphonic acid was detectable in the brains of 3xTg-AD and NonTg glyphosate-dosed mice despite the 6-month recovery. Glyphosate-dosed 3xTg-AD mice showed reduced survival, increased thigmotaxia in the Morris water maze, significant increases in the beta secretase enzyme (BACE-1) of amyloidogenic processing, amyloid-β (Aβ) 42 insoluble fractions, Aβ 42 plaque load and plaque size, and phosphorylated tau (pTau) at epitopes Threonine 181, Serine 396, and AT8 (Serine 202, Threonine 205). Notably, we found increased pro- and anti-inflammatory cytokines and chemokines persisting in both 3xTg-AD and NonTg brain tissue and in 3xTg-AD peripheral blood plasma.</p><p><strong>Conclusion: </strong>Taken together, our results are the first to demonstrate that despite an extended recovery period, exposure to glyphosate elicits long-lasting pathological consequences. As glyphosate use continues to rise, more research is needed to elucidate the impact of this herbicide and its metabolites on the human brain, and their potential to contribute to dysfunctions observed in neurodegenerative diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"316"},"PeriodicalIF":9.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoantibody profiles in Alzheimer´s, Parkinson´s, and dementia with Lewy bodies: altered IgG affinity and IgG/IgM/IgA responses to alpha-synuclein, amyloid-beta, and tau in disease-specific pathological patterns.","authors":"Luisa Knecht, Katrine Dalsbøl, Anja Hviid Simonsen, Falk Pilchner, Jean Alexander Ross, Kristian Winge, Lisette Salvesen, Sara Bech, Anne-Mette Hejl, Annemette Løkkegaard, Steen G Hasselbalch, Richard Dodel, Susana Aznar, Gunhild Waldemar, Tomasz Brudek, Jonas Folke","doi":"10.1186/s12974-024-03293-3","DOIUrl":"10.1186/s12974-024-03293-3","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative disorders marked by protein aggregation, with AD featuring amyloid-beta (Aβ) and tau proteins, and PD alpha-synuclein (αSyn). Dementia with Lewy bodies (DLB) often presents with a mix of these pathologies. This study explores naturally occurring autoantibodies (nAbs), including Immunoglobulin (Ig)G, IgM, and IgA, which target αSyn, Aβ and tau to maintain homeostasis and were previously found altered in AD and PD patients, among others.</p><p><strong>Main text: </strong>We extended this investigation across AD, PD and DLB patients investigating both the affinities of IgGs and levels of IgGs, IgMs and IgAs towards αSyn, Aβ and tau utilizing chemiluminescence assays. We confirmed that AD and PD patients exhibited lower levels of high-affinity anti-Aβ and anti-αSyn IgGs, respectively, than healthy controls. AD patients also showed diminished levels of high-affinity anti-αSyn IgGs, while anti-tau IgG affinities did not differ significantly across groups. However, DLB patients exhibited increased anti-αSyn IgG but decreased anti-αSyn IgM levels compared to controls and PD patients, with AD patients showing a similar pattern. Interestingly, AD patients had higher anti-Aβ IgG but lower anti-Aβ IgA levels than DLB patients. DLB patients had reduced anti-Aβ IgM levels compared to controls, and anti-tau IgG levels were lower in AD than PD patients, who had reduced anti-tau IgM levels compared to controls. AD patients uniquely showed higher anti-tau IgA levels. Significant correlations were observed between clinical measures and nAbs, with negative correlations between anti-αSyn IgG affinity and levels in DLB patients and a positive correlation with anti-αSyn IgA levels in PD patients. Disease-specific changes in nAb levels and affinity correlations were identified, highlighting altered immune responses.</p><p><strong>Conclusion: </strong>This study reveals distinctive nAb profiles in AD, DLB, and PD, pinpointing specific immune deficiencies against pathological proteins. These insights into the autoreactive immune system's role in neurodegeneration suggest nAbs as potential markers for vulnerability to protein aggregation, offering new avenues for understanding and possibly diagnosing these conditions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"317"},"PeriodicalIF":9.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ketogenic diet modulates immune cell transcriptional landscape and ameliorates experimental autoimmune uveitis in mice.","authors":"Runping Duan, Tianfu Wang, Zhaohuai Li, Loujing Jiang, Xiaoyang Yu, Daquan He, Tianyu Tao, Xiuxing Liu, Zhaohao Huang, Lei Feng, Wenru Su","doi":"10.1186/s12974-024-03308-z","DOIUrl":"10.1186/s12974-024-03308-z","url":null,"abstract":"<p><strong>Background: </strong>Uveitis manifests as immune-mediated inflammatory disorders within the eye, posing a serious threat to vision. The ketogenic diet (KD) has emerged as a promising dietary intervention, yet its impact on the immune microenvironments and role in uveitis remains unclear.</p><p><strong>Methods: </strong>Utilizing single-cell RNA sequencing (scRNA-seq) data from lymph node and retina of mice, we conduct a comprehensive investigation into the effects of KD on immune microenvironments. Flow cytometry is conducted to verify the potential mechanisms.</p><p><strong>Results: </strong>This study demonstrates that KD alters the composition and function of immune profiles. Specifically, KD promotes the differentiation of Treg cells and elevates its proportion in heathy mice. In response to experimental autoimmune uveitis challenges, KD alleviates the inflammatory symptoms, lowers CD4⁺ T cell pathogenicity, and corrects the Th17/Treg imbalance. Additionally, KD decreases the proportion of Th17 cell and increases Treg cells in the retina. Analysis of combined retinal and CDLN immune cells reveals that retinal immune cells, particularly CD4⁺ T cells, exhibit heightened inflammatory responses, which KD partially reverses.</p><p><strong>Conclusions: </strong>The KD induces inhibitory structural and functional alterations in immune cells from lymph nodes to retina, suggesting its potential as a therapy for uveitis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"319"},"PeriodicalIF":9.3,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}