Journal of Neuroinflammation最新文献

{"title":"IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease.","authors":"Radhika Joshi, Veronika Brezani, Gabrielle M Mey, Sergi Guixé-Muntet, Marti Ortega-Ribera, Yuan Zhuang, Adam Zivny, Sebastian Werneburg, Jordi Gracia-Sancho, Gyongyi Szabo","doi":"10.1186/s12974-024-03203-7","DOIUrl":"10.1186/s12974-024-03203-7","url":null,"abstract":"<p><p>The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D: IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer's disease, notably apolipoprotein-e. Using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 (ZBP1) as a target of IRF3 that is relevant across various neuroinflammatory disorders. Lastly, we show IRF3 phosphorylation and IRF3-dependent ZBP1 induction in response to Aβ in primary microglia cultures. Together, our results identify IRF3 as an important regulator of LPS and Aβ -mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108361","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":"Systemic inflammation following traumatic injury and its impact on neuroinflammatory gene expression in the rodent brain.","authors":"Cassie J Rowe, Uloma Nwaolu, Laura Martin, Benjamin J Huang, Josef Mang, Daniela Salinas, Cody D Schlaff, Sennay Ghenbot, Jefferson L Lansford, Benjamin K Potter, Seth A Schobel, Eric R Gann, Thomas A Davis","doi":"10.1186/s12974-024-03205-5","DOIUrl":"10.1186/s12974-024-03205-5","url":null,"abstract":"<p><strong>Background: </strong>Trauma can result in systemic inflammation that leads to organ dysfunction, but the impact on the brain, particularly following extracranial insults, has been largely overlooked.</p><p><strong>Methods: </strong>Building upon our prior findings, we aimed to understand the impact of systemic inflammation on neuroinflammatory gene transcripts in eight brain regions in rats exposed to (1) blast overpressure exposure [BOP], (2) cutaneous thermal injury [BU], (3) complex extremity injury, 3 hours (h) of tourniquet-induced ischemia, and hind limb amputation [CEI+tI+HLA], (4) BOP+BU or (5) BOP+CEI and delayed HLA [BOP+CEI+dHLA] at 6, 24, and 168 h post-injury (hpi).</p><p><strong>Results: </strong>Globally, the number and magnitude of differentially expressed genes (DEGs) correlated with injury severity, systemic inflammation markers, and end-organ damage, driven by several chemokines/cytokines (Csf3, Cxcr2, Il16, and Tgfb2), neurosteroids/prostaglandins (Cyp19a1, Ptger2, and Ptger3), and markers of neurodegeneration (Gfap, Grin2b, and Homer1). Regional neuroinflammatory activity was least impacted following BOP. Non-blast trauma (in the BU and CEI+tI+HLA groups) contributed to an earlier, robust and diverse neuroinflammatory response across brain regions (up to 2-50-fold greater than that in the BOP group), while combined trauma (in the BOP+CEI+dHLA group) significantly advanced neuroinflammation in all regions except for the cerebellum. In contrast, BOP+BU resulted in differential activity of several critical neuroinflammatory-neurodegenerative markers compared to BU. t-SNE plots of DEGs demonstrated that the onset, extent, and duration of the inflammatory response are brain region dependent. Regardless of injury type, the thalamus and hypothalamus, which are critical for maintaining homeostasis, had the most DEGs. Our results indicate that neuroinflammation in all groups progressively increased or remained at peak levels over the study duration, while markers of end-organ dysfunction decreased or otherwise resolved.</p><p><strong>Conclusions: </strong>Collectively, these findings emphasize the brain's sensitivity to mediators of systemic inflammation and provide an example of immune-brain crosstalk. Follow-on molecular and behavioral investigations are warranted to understand the short- to long-term pathophysiological consequences on the brain, particularly the mechanism of blood-brain barrier breakdown, immune cell penetration-activation, and microglial activation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11360339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093532","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":"Suppression of inner blood-retinal barrier breakdown and pathogenic Müller glia activation in ischemia retinopathy by myeloid cell depletion.","authors":"Lingli Zhou, Zhenhua Xu, Haining Lu, Hongkwan Cho, Yangyiran Xie, Grace Lee, Kaoru Ri, Elia J Duh","doi":"10.1186/s12974-024-03190-9","DOIUrl":"10.1186/s12974-024-03190-9","url":null,"abstract":"<p><p>Ischemic retinopathies including diabetic retinopathy are major causes of vision loss. Inner blood-retinal barrier (BRB) breakdown with retinal vascular hyperpermeability results in macular edema. Although dysfunction of the neurovascular unit including neurons, glia, and vascular cells is now understood to underlie this process, there is a need for fuller elucidation of the underlying events in BRB dysfunction in ischemic disease, including a systematic analysis of myeloid cells and exploration of cellular cross-talk. We used an approach for microglia depletion with the CSF-1R inhibitor PLX5622 (PLX) in the retinal ischemia-reperfusion (IR) model. Under non-IR conditions, PLX treatment successfully depleted microglia in the retina. PLX suppressed the microglial activation response following IR as well as infiltration of monocyte-derived macrophages. This occurred in association with reduction of retinal expression of chemokines including CCL2 and the inflammatory adhesion molecule ICAM-1. In addition, there was a marked suppression of retinal neuroinflammation with reduction in expression of IL-1b, IL-6, Ptgs2, TNF-a, and Angpt2, a protein that regulates BRB permeability. PLX treatment significantly suppressed inner BRB breakdown following IR, without an appreciable effect on neuronal dysfunction. A translatomic analysis of Müller glial-specific gene expression in vivo using the Ribotag approach demonstrated a strong suppression of Müller cell expression of multiple pro-inflammatory genes following PLX treatment. Co-culture studies of Müller cells and microglia demonstrated that activated microglia directly upregulates Müller cell-expression of these inflammatory genes, indicating Müller cells as a downstream effector of myeloid cells in retinal IR. Co-culture studies of these two cell types with endothelial cells demonstrated the ability of both activated microglia and Müller cells to compromise EC barrier function. Interestingly, quiescent Müller cells enhanced EC barrier function in this co-culture system. Together this demonstrates a pivotal role for myeloid cells in inner BRB breakdown in the setting of ischemia-associated disease and indicates that myeloid cells play a major role in iBRB dysregulation, through direct and indirect effects, while Müller glia participate in amplifying the neuroinflammatory effect of myeloid cells.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055835","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":"Tet1-mediated 5hmC regulates hippocampal neuroinflammation via wnt signaling as a novel mechanism in obstructive sleep apnoea leads to cognitive deficit.","authors":"Yaru Kong, Jie Ji, Xiaojun Zhan, Weiheng Yan, Fan Liu, Pengfei Ye, Shan Wang, Jun Tai","doi":"10.1186/s12974-024-03189-2","DOIUrl":"10.1186/s12974-024-03189-2","url":null,"abstract":"<p><strong>Background: </strong>Obstructive sleep apnoea (OSA) is a sleep-disordered breathing characterized by intermittent hypoxia (IH) that may cause cognitive dysfunction. However, the impact of IH on molecular processes involved in cognitive function remains unclear.</p><p><strong>Methods: </strong>C57BL / 6 J mice were exposed to either normoxia (control) or IH for 6 weeks. DNA hydroxymethylation was quantified by hydroxymethylated DNA immunoprecipitation (hMeDIP) sequencing. ten-eleven translocation 1 (Tet1) was knocked down by lentivirus. Specifically, cognitive function was assessed by behavioral experiments, pathological features were assessed by HE staining, the hippocampal DNA hydroxymethylation was examined by DNA dot blot and immunohistochemical staining, while the Wnt signaling pathway and its downstream effects were studied using qRT-PCR, immunofluorescence staining, and Luminex liquid suspension chip analysis.</p><p><strong>Results: </strong>IH mice showed pathological changes and cognitive dysfunction in the hippocampus. Compared with the control group, IH mice exhibited global DNA hydroxylmethylation in the hippocampus, and the expression of three hydroxylmethylases increased significantly. The Wnt signaling pathway was activated, and the mRNA and 5hmC levels of Wnt3a, Ccnd2, and Prickle2 were significantly up-regulated. Further caused downstream neurogenesis abnormalities and neuroinflammatory activation, manifested as increased expression of IBA1 (a marker of microglia), GFAP (a marker of astrocytes), and DCX (a marker of immature neurons), as well as a range of inflammatory cytokines (e.g. TNFa, IL3, IL9, and IL17A). After Tet1 knocked down, the above indicators return to normal.</p><p><strong>Conclusion: </strong>Activation of Wnt signaling pathway by hippocampal Tet1 is associated with cognitive dysfunction induced by IH.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017721","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":"The contribution of tumor necrosis factor to multiple sclerosis: a possible role in progression independent of relapse?","authors":"Valentina Mazziotti, Francesco Crescenzo, Ermanna Turano, Maddalena Guandalini, Maddalena Bertolazzo, Stefano Ziccardi, Federica Virla, Valentina Camera, Damiano Marastoni, Agnese Tamanti, Massimiliano Calabrese","doi":"10.1186/s12974-024-03193-6","DOIUrl":"10.1186/s12974-024-03193-6","url":null,"abstract":"<p><p>Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017722","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":"The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain.","authors":"Melanie Ohm, Shirin Hosseini, Niklas Lonnemann, Wei He, Tushar More, Oliver Goldmann, Eva Medina, Karsten Hiller, Martin Korte","doi":"10.1186/s12974-024-03188-3","DOIUrl":"10.1186/s12974-024-03188-3","url":null,"abstract":"<p><p>Despite advances in antimicrobial and anti-inflammatory treatment, inflammation and its consequences remain a major challenge in the field of medicine. Inflammatory reactions can lead to life-threatening conditions such as septic shock, while chronic inflammation has the potential to worsen the condition of body tissues and ultimately lead to significant impairment of their functionality. Although the central nervous system has long been considered immune privileged to peripheral immune responses, recent research has shown that strong immune responses in the periphery also affect the brain, leading to reactive microglia, which belong to the innate immune system and reside in the brain, and neuroinflammation. The inflammatory response is primarily a protective mechanism to defend against pathogens and tissue damage. However, excessive and chronic inflammation can have negative effects on neuronal structure and function. Neuroinflammation underlies the pathogenesis of many neurological and neurodegenerative diseases and can accelerate their progression. Consequently, targeting inflammatory signaling pathways offers potential therapeutic strategies for various neuropathological conditions, particularly Parkinson's and Alzheimer's disease, by curbing inflammation. Here the blood-brain barrier is a major hurdle for potential therapeutic strategies, therefore it would be highly advantageous to foster and utilize brain innate anti-inflammatory mechanisms. The tricarboxylic acid cycle-derived metabolite itaconate is highly upregulated in activated macrophages and has been shown to act as an immunomodulator with anti-inflammatory and antimicrobial functions. Mesaconate, an isomer of itaconate, similarly reduces the inflammatory response in macrophages. Nevertheless, most studies have focused on its esterified forms and its peripheral effects, while its influence on the CNS remained largely unexplored. Therefore, this study investigated the immunomodulatory and therapeutic potential of endogenously synthesized itaconate and its isomer mesaconate in lipopolysaccharide (LPS)-induced neuroinflammatory processes. Our results show that both itaconate and mesaconate reduce LPS-induced neuroinflammation, as evidenced by lower levels of inflammatory mediators, reduced microglial reactivity and a rescue of synaptic plasticity, the cellular correlate of learning and memory processes in the brain. Overall, this study emphasizes that both itaconate and mesaconate have therapeutic potential for neuroinflammatory processes in the brain and are of remarkable importance due to their endogenous origin and production, which usually leads to high tolerance.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008958","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":"CB2 expression in mouse brain: from mapping to regulation in microglia under inflammatory conditions.","authors":"Wanda Grabon, Anne Ruiz, Nadia Gasmi, Cyril Degletagne, Béatrice Georges, Amor Belmeguenai, Jacques Bodennec, Sylvain Rheims, Guillaume Marcy, Laurent Bezin","doi":"10.1186/s12974-024-03202-8","DOIUrl":"10.1186/s12974-024-03202-8","url":null,"abstract":"<p><p>Since its detection in the brain, the cannabinoid receptor type 2 (CB2) has been considered a promising therapeutic target for various neurological and psychiatric disorders. However, precise brain mapping of its expression is still lacking. Using magnetic cell sorting, calibrated RT-qPCR and single-nucleus RNAseq, we show that CB2 is expressed at a low level in all brain regions studied, mainly by few microglial cells, and by neurons in an even lower proportion. Upon lipopolysaccharide stimulation, modeling neuroinflammation in non-sterile conditions, we demonstrate that the inflammatory response is associated with a transient reduction in CB2 mRNA levels in brain tissue, particularly in microglial cells. This result, confirmed in the BV2 microglial cell line, contrasts with the positive correlation observed between CB2 mRNA levels and the inflammatory response upon stimulation by interferon-gamma, modeling neuroinflammation in sterile condition. Discrete brain CB2 expression might thus be up- or down-regulated depending on the inflammatory context.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004430","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":"The differential proteomic response to ischemic stroke in appalachian subjects treated with mechanical thrombectomy.","authors":"Christopher J McLouth, Benton Maglinger, Jacqueline A Frank, Hunter S Hazelwood, Jordan P Harp, Will Cranford, Shivani Pahwa, Lila Sheikhi, David Dornbos, Amanda L Trout, Ann M Stowe, Justin F Fraser, Keith R Pennypacker","doi":"10.1186/s12974-024-03201-9","DOIUrl":"10.1186/s12974-024-03201-9","url":null,"abstract":"<p><strong>Introduction: </strong>The Appalachia region of North America is known to have significant health disparities, specifically, worse risk factors and outcomes for stroke. Appalachians are more likely to have comorbidities related to stroke, such as diabetes, obesity, and tobacco use, and are often less likely to have stroke interventions, such as mechanical thrombectomy (MT), for emergent large vessel occlusion (ELVO). As our Comprehensive Stroke Center directly serves stroke subjects from both Appalachian and non-Appalachian areas, inflammatory proteomic biomarkers were identified associated with stroke outcomes specific to subjects residing in Appalachia.</p><p><strong>Methods: </strong>There were 81 subjects that met inclusion criteria for this study. These subjects underwent MT for ELVO, and carotid arterial blood samples acquired at time of intervention were sent for proteomic analysis. Samples were processed in accordance with the Blood And Clot Thrombectomy Registry And Collaboration (BACTRAC; clinicaltrials.gov; NCT03153683). Statistical analyses were utilized to examine whether relationships between protein expression and outcomes differed by Appalachian status for functional (NIH Stroke Scale; NIHSS and Modified Rankin Score; mRS), and cognitive outcomes (Montreal Cognitive Assessment; MoCA).</p><p><strong>Results: </strong>No significant differences were found in demographic data or co-morbidities when comparing Appalachian to non-Appalachian subjects. However, time from stroke onset to treatment (last known normal) was significantly longer and edema volume significantly higher in patients from Appalachia. Further, when comparing Appalachian to non-Appalachian subjects, there were significant unadjusted differences in the NIHSS functional outcome. A comprehensive analysis of 184 proteins from Olink proteomic (92 Cardiometabolic and 92 Inflammation panels) showed that the association between protein expression outcomes significantly differed by Appalachian status for seven proteins for the NIHSS, two proteins for the MoCA, and three for the mRS.</p><p><strong>Conclusion: </strong>Our study utilizes an ELVO tissue bank and registry to investigate the intracranial/intravascular proteomic environment occurring at the time of thrombectomy. We found that patients presenting from Appalachian areas have different levels of proteomic expression at the time of MT when compared to patients presenting from non-Appalachian areas. These proteins differentially relate to stroke outcome and could be used as prognostic biomarkers, or as targets for novel therapies. The identification of a disparate proteomic response in Appalachian patients provides initial insight to the biological basis for health disparity. Nevertheless, further investigations through community-based studies are imperative to elucidate the underlying causes of this differential response.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995920","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":"Retraction Note: Inhibiting the microglia activation improves the spatial memory and adult neurogenesis in rat hippocampus during 48 h of sleep deprivation.","authors":"Meetu Wadhwa, Amit Prabhakar, Koushik Ray, Koustav Roy, Punita Kumari, Prabhash Kumar Jha, Krishna Kishore, Sanjeev Kumar, Usha Panjwani","doi":"10.1186/s12974-024-03200-w","DOIUrl":"10.1186/s12974-024-03200-w","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995919","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":"Deterioration of neuroimmune homeostasis in Alzheimer's Disease patients who survive a COVID-19 infection.","authors":"Jonathan A B Villareal, Tim Bathe, Gabriela P Hery, Jennifer L Phillips, Wangchen Tsering, Stefan Prokop","doi":"10.1186/s12974-024-03196-3","DOIUrl":"10.1186/s12974-024-03196-3","url":null,"abstract":"<p><p>Growing evidence has implicated systemic infection as a significant risk factor for the development and advancement of Alzheimer's disease (AD). With the emergence of SARS-CoV-2 (COVID-19) and the resultant pandemic, many individuals from the same aging population vulnerable to AD suffered a severe systemic infection with potentially unidentified long-term consequences for survivors. To study the impact of COVID-19 survival on the brain's intrinsic immune system in a population also suffering from AD, we profiled post-mortem brain tissue from patients in the UF Neuromedicine Human Brain and Tissue Bank with a diagnosis of AD who survived a COVID-19 infection (COVID-AD) and contrasted our findings with AD patients who did not experience a COVID-19 infection, including a group of brain donors who passed away before arrival of SARS-CoV-2 in the United States. We assessed disease-relevant protein pathology and microglial and astrocytic markers by quantitative immunohistochemistry and supplemented these data with whole tissue gene expression analysis performed on the NanoString nCounter^® platform. COVID-AD patients showed slightly elevated Aβ burden in the entorhinal, fusiform, and inferior temporal cortices compared to non-COVID-AD patients, while tau pathology burden did not differ between groups. Analysis of microglia revealed a significant loss of microglial homeostasis as well as exacerbated microgliosis in COVID-AD patients compared to non-COVID-AD patients in a brain region-dependent manner. Furthermore, COVID-AD patients showed reduced cortical astrocyte numbers, independent of functional subtype. Transcriptomic analysis supported these histological findings and, in addition, identified a dysregulation of oligodendrocyte and myelination pathways in the hippocampus of COVID-AD patients. In summary, our data demonstrate a profound impact of COVID-19 infection on neuroimmune and glial pathways in AD patients persisting for months post-infection, highlighting the importance of peripheral to central neuroimmune crosstalk in neurodegenerative diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995918","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}