Experimental Neurology最新文献

{"title":"Exploring the potential of routine serological markers in predicting neurological outcomes in spinal cord injury","authors":"Jan Matthias, Louis P. Lukas, Sarah C. Brüningk, Doris Maier, O. Mach, L. Grassner, John L.K. Kramer, L. Bourguignon, C. Jutzeler","doi":"10.1016/j.expneurol.2024.114918","DOIUrl":"https://doi.org/10.1016/j.expneurol.2024.114918","url":null,"abstract":"","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the molecular mechanisms of Ace2-mediated post-COVID-19 cognitive dysfunction through systems genetics approach","authors":"","doi":"10.1016/j.expneurol.2024.114921","DOIUrl":"10.1016/j.expneurol.2024.114921","url":null,"abstract":"<div><p>The dysregulation of Angiotensin-converting enzyme 2 (ACE2) in central nervous system is believed associates with COVID-19 induced cognitive dysfunction. However, the detailed mechanism remains largely unknown. In this study, we performed a comprehensive system genetics analysis on hippocampal <em>ACE2</em> based on BXD mice panel. Expression quantitative trait loci (eQTLs) mapping showed that <em>Ace2</em> was strongly trans-regulated, and the elevation of <em>Ace2</em> expression level was significantly correlated with impaired cognitive functions. Further Gene co-expression analysis showed that <em>Ace2</em> may be correlated with the membrane proteins in Calcium signaling pathway. Further, qRT-PCR confirmed that SARS-CoV-2 spike S1 protein upregulated <em>ACE2</em> expression together with eight membrane proteins in Calcium Signaling pathway. Moreover, such elevation can be attenuated by recombinant <em>ACE2</em>. Collectively, our findings revealed a potential mechanism of <em>Ace2</em> in cognitive dysfunction, which could be beneficial for COVID–19–induced cognitive dysfunction prevention and potential treatment.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights into COVID-19 pathophysiology from a longitudinal multisystem report during acute infection","authors":"","doi":"10.1016/j.expneurol.2024.114917","DOIUrl":"10.1016/j.expneurol.2024.114917","url":null,"abstract":"<div><p>The Coronavirus disease 2019 (COVID-19), an illness caused by a SARS-CoV-2 viral infection, has been associated with neurological and neuropsychiatric disorders, revealing its impact beyond the respiratory system. Most related research involved individuals with post-acute or persistent symptoms of COVID-19, also referred to as long COVID or Post-Acute Sequelae of COVID-19 (PASC). In this longitudinal unique report, we aimed to describe the acute supraspinal and corticospinal changes and functional alterations induced by a COVID-19 infection using neuroimaging, neurophysiological and clinical assessment of a participant during acute infection, as compared to three other visits where the participant had no COVID-19. The results favor a multisystem impairment, impacting cortical activity, functional connectivity, and corticospinal excitability, as well as motor and cardiovascular function. The report suggests pathophysiological alteration and impairment already present at the acute stage, that if resolved tend to lead to a full clinical recovery. Such results could be also insightful into PASC symptomatology.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002437/pdfft?md5=d9ff6992886e9b4c583b1f00e94fb5f2&pid=1-s2.0-S0014488624002437-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM21-mediated ubiquitination of PLIN2 regulates neuronal lipid droplet accumulation after acute spinal cord injury","authors":"","doi":"10.1016/j.expneurol.2024.114916","DOIUrl":"10.1016/j.expneurol.2024.114916","url":null,"abstract":"<div><p>To investigate the changes in neuronal lipid droplet (LD) accumulation and lipid metabolism after acute spinal cord injury (SCI), we established a rat model of compressive SCI. Oil Red O staining, BODIPY 493/503 staining, and 4-hydroxynonenal immunofluorescence staining were performed to determine overall LD accumulation, neuronal LD accumulation, and lipid peroxidation. Lipidomics was conducted to identify the lipid components in the local SCI microenvironment. We focused on the expression and regulation of perilipin 2 (PLIN2) and knocked down PLIN2 <em>in vivo</em> by intrathecal injection of adeno-associated virus 9–synapsin–short-hairpin RNA-PLIN2 (<em>AAV9-SYN-shPlin2</em>). Motor function was assessed using the Basso–Beattie–Bresnahan score. Proteins that interacted with PLIN2 were screened by immunoprecipitation (IP) and qualitative shotgun proteomics, and confirmed by co-IP. A ubiquitination assay was performed to validate whether ubiquitination was involved in PLIN2 degradation. Oil Red O staining indicated that LDs steadily accumulated after SCI. Fluorescent staining indicated the accumulation of LDs in neurons with increased lipid peroxidation. Lipidomics revealed significant changes in lipid components after SCI. PLIN2 expression significantly increased following SCI, and knockdown of PLIN2 using <em>AAV9-SYN-Plin2</em> reduced neuronal LD accumulation. This intervention improved the neuronal survival and motor function of injured rats. IP and qualitative shotgun proteomics identified tripartite motif-containing protein 21 (TRIM21) as a direct binding protein of PLIN2, and this interaction was confirmed by co-IP <em>in vitro</em> and immunofluorescence staining <em>in vivo</em>. By manipulating TRIM21 expression, we found it was negatively correlated with PLIN2 expression. In conclusion, PLIN2 is involved in neuronal LD accumulation following SCI. TRIM21 mediated the ubiquitination and degradation of PLIN2 in neurons. Inhibition of PLIN2 enhanced the recovery of motor function after SCI.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocyte-derived lipocalin 2 promotes inflammation and scarring after spinal cord injury by activating SMAD in mice","authors":"","doi":"10.1016/j.expneurol.2024.114915","DOIUrl":"10.1016/j.expneurol.2024.114915","url":null,"abstract":"<div><h3>Background</h3><p>The inflammatory response and scar formation after spinal cord injury (SCI) limit nerve regeneration and functional recovery. Our research group has previously shown that the expression of astrocyte-derived lipocalin 2 (Lcn2) is upregulated after SCI, which correlates with neuronal apoptosis and functional recovery. Therefore, we speculate that astrocyte-specific knockdown of Lcn2 after SCI may lead to a better prognosis.</p></div><div><h3>Methods</h3><p>Tissue RNA sequencing, Western blotting, PCR, and immunofluorescence assays were conducted to assess the expression of Lcn2 following SCI in mice. Adeno-associated virus 9 (AAV9) transfection was employed to specifically reduce the expression of Lcn2 in astrocytes, and subsequent evaluations of scarring and inflammation were conducted. In vitro experiments involved treating primary astrocytes with TGF-β or an A1-induced mixture (C1q, TNF-α and IL-1α) following Lcn2 knockdown. Finally, the intrathecal injection of recombinant Lcn2 (ReLcn2) protein was conducted post-injury to further confirm the role of Lcn2 and its underlying mechanism in SCI.</p></div><div><h3>Results</h3><p>Lcn2 expression was elevated in astrocytes after SCI at 7 dpi (days post injury). Lcn2 knockdown in astrocytes is beneficial for neuronal survival and functional recovery after SCI, and is accompanied by a reduced inflammatory response and inhibited scar formation. The inhibition of SMAD-associated signaling activation was identified as a possible mechanism, and in vitro experiments further confirmed this finding. ReLcn2 further activated SMAD-associated signaling and aggravated motor function after SCI.</p></div><div><h3>Conclusion</h3><p>The upregulation of Lcn2 expression in astrocytes is involved in neuroinflammation and scar formation after SCI, and the activation of SMAD-associated signaling is one of the underlying mechanisms.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated multi-omics analysis reveals molecular changes associated with chronic lipid accumulation following contusive spinal cord injury","authors":"","doi":"10.1016/j.expneurol.2024.114909","DOIUrl":"10.1016/j.expneurol.2024.114909","url":null,"abstract":"<div><p>Functional and pathological recovery after spinal cord injury (SCI) is often incomplete due to the limited regenerative capacity of the central nervous system (CNS), which is further impaired by several mechanisms that sustain tissue damage. Among these, the chronic activation of immune cells can cause a persistent state of local CNS inflammation and damage. However, the mechanisms that sustain this persistent maladaptive immune response in SCI have not been fully clarified yet.</p><p>In this study, we integrated histological analyses with proteomic, lipidomic, transcriptomic, and epitranscriptomic approaches to study the pathological and molecular alterations that develop in a mouse model of cervical spinal cord hemicontusion.</p><p>We found significant pathological alterations of the lesion rim with myelin damage and axonal loss that persisted throughout the late chronic phase of SCI. This was coupled by a progressive lipid accumulation in myeloid cells, including resident microglia and infiltrating monocyte-derived macrophages. At tissue level, we found significant changes of proteins indicative of glycolytic, tricarboxylic acid cycle (TCA), and fatty acid metabolic pathways with an accumulation of triacylglycerides with C16:0 fatty acyl chains in chronic SCI. Following transcriptomic, proteomic, and epitranscriptomic studies identified an increase of cholesterol and m⁶A methylation in lipid-droplet-accumulating myeloid cells as a core feature of chronic SCI.</p><p>By characterizing the multiple metabolic pathways altered in SCI, our work highlights a key role of lipid metabolism in the chronic response of the immune and central nervous system to damage.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002358/pdfft?md5=10302c2866f08a62bdd7ad64c744a1e5&pid=1-s2.0-S0014488624002358-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating therapeutic nonsense suppression in a neurofibromatosis mouse model","authors":"","doi":"10.1016/j.expneurol.2024.114914","DOIUrl":"10.1016/j.expneurol.2024.114914","url":null,"abstract":"<div><p>Neurofibromatosis type 1 (NF1) is a human genetic disorder caused by variants in the <em>NF1</em> gene. Plexiform neurofibromas, one of many NF1 manifestations, are benign peripheral nerve sheath tumors occurring in up to 50% of NF1 patients. A substantial fraction of <em>NF1</em> pathogenetic variants are nonsense mutations, which result in the synthesis of truncated non-functional NF1 protein (neurofibromin). To date, no therapeutics have restored neurofibromin expression or addressed the consequences of this protein's absence in NF1 nonsense mutation patients, but nonsense suppression is a potential approach to the problem. Ataluren is a small molecule drug that has been shown to stimulate functional nonsense codon readthrough in several models of nonsense mutation diseases, as well as in Duchenne muscular dystrophy patients. To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C &gt; T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female <em>Nf1</em>-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002401/pdfft?md5=123a8ac0b73013ac7c3d9b34f7877191&pid=1-s2.0-S0014488624002401-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of segmental motor outcomes in traumatic spinal cord injury: Advances beyond sum scores","authors":"","doi":"10.1016/j.expneurol.2024.114905","DOIUrl":"10.1016/j.expneurol.2024.114905","url":null,"abstract":"<div><h3>Background and objectives</h3><p>Neurological and functional recovery after traumatic spinal cord injury (SCI) is highly challenged by the level of the lesion and the high heterogeneity in severity (different degrees of in/complete SCI) and spinal cord syndromes (hemi-, ant-, central-, and posterior cord). So far outcome predictions in clinical trials are limited in targeting sum motor scores of the upper (UEMS) and lower limb (LEMS) while neglecting that the distribution of motor function is essential for functional outcomes. The development of data-driven prediction models of detailed segmental motor recovery for all spinal segments from the level of lesion towards the lowest motor segments will improve the design of rehabilitation programs and the sensitivity of clinical trials.</p></div><div><h3>Methods</h3><p>This study used acute-phase International Standards for Neurological Classification of SCI exams to forecast 6-month recovery of segmental motor scores as the primary evaluation endpoint. Secondary endpoints included severity grade improvement, independent walking, and self-care ability. Different similarity metrics were explored for k-nearest neighbor (kNN) matching within 1267 patients from the European Multicenter Study about Spinal Cord Injury before validation in 411 patients from the Sygen trial. The kNN performance was compared to linear and logistic regression models.</p></div><div><h3>Results</h3><p>We obtained a population-wide root-mean-squared error (RMSE) in motor score sequence of 0.76(0.14, 2.77) and competitive functional score predictions (AUC_walker = 0.92, AUC_self-carer = 0.83) for the kNN algorithm, improving beyond the linear regression task (RMSE_linear = 0.98(0.22, 2.57)). The validation cohort showed comparable results (RMSE = 0.75(0.13, 2.57), AUC_walker = 0.92). We deploy the final historic control model as a web tool for easy user interaction (<span><span>https://hicsci.ethz.ch/</span><svg><path></path></svg></span>).</p></div><div><h3>Discussion</h3><p>Our approach is the first to provide predictions across all motor segments independent of the level and severity of SCI. We provide a machine learning concept that is highly interpretable, i.e. the prediction formation process is transparent, that has been validated across European and American data sets, and provides reliable and validated algorithms to incorporate external control data to increase sensitivity and feasibility of multinational clinical trials.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002310/pdfft?md5=8701ffd4c042068c4f69030561172100&pid=1-s2.0-S0014488624002310-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALKBH5 deficiency attenuates oxygen-glucose deprivation-induced injury in mouse brain microvascular endothelial cells in an m6A dependent manner","authors":"","doi":"10.1016/j.expneurol.2024.114910","DOIUrl":"10.1016/j.expneurol.2024.114910","url":null,"abstract":"<div><p>Structural and functional alterations in brain microvascular endothelial cells (BMECs) caused by oxygen-glucose deprivation (OGD) are involved in the pathogenesis of various brain disorders. AlkB homolog 5 (ALKBH5) is a primary m6A demethylase that regulates various cell processes, but its distinct roles in BMEC function remain to be clarified. In the present study, in mouse middle cerebral artery occlusion (MCAO) model, knockout of ALKBH5 reduced neurological deficits, infarct volumes and tissue apoptosis caused by ischemia/reperfusion injury. Evans blue leakage and decreased expression of the tight junction protein ZO-1 and Occludin were also attenuated by ALKBH5 knockout. During the exploration of the underlying mechanisms of the role of ALKBH5 in BMECs, we found that the expression of ALKBH5 was induced at both the mRNA and protein levels by hypoxia; however, its protein stability was impaired by OGD treatment. Knockdown of ALKBH5 expression increased total m6A levels and alleviated OGD-induced BMEC injury. At the same time, the selective ALKBH5 inhibitor Cpd 20m also exhibited a protective effect on cell injury. In contrast, overexpression of ALKBH5 increased the sensitivity of BMECs to OGD. Interestingly, the m6A sequencing data revealed that knockdown of ALKBH5altered the expression of many genes via m6A upregulation. The gene expression alterations were verified by real-time PCR. Taken together, our results suggest that ALKBH5, as well as its target genes, plays important roles in the regulation of brain microvascular endothelial cell function through its RNA demethylase activity.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S001448862400236X/pdfft?md5=c2e82ce6929b8f431d31835cf4324616&pid=1-s2.0-S001448862400236X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral hypoperfusion exacerbates vascular dysfunction after traumatic brain injury","authors":"","doi":"10.1016/j.expneurol.2024.114907","DOIUrl":"10.1016/j.expneurol.2024.114907","url":null,"abstract":"<div><p>Traumatic brain injuries are extremely common, and although most patients recover from their injuries many TBI patients suffer prolonged symptoms and remain at a higher risk for developing cardiovascular disease and neurodegeneration. Moreover, it remains challenging to identify predictors of poor long-term outcomes. Here, we tested the hypothesis that preexisting cerebrovascular impairment exacerbates metabolic and vascular dysfunction and leads to worse outcomes after TBI. Male mice underwent a mild surgical reduction in cerebral blood flow using a model of bilateral carotid artery stenosis (BCAS) wherein steel microcoils were implanted around the carotid arteries. Then, 30 days post coil implantation, mice underwent TBI or sham surgery. Gene expression profiles, cerebral blood flow, metabolic function, oxidative damage, vascular health and angiogenesis were assessed. Single nuclei RNA sequencing of endothelial cells isolated from mice after TBI showed differential gene expression profiles after TBI and BCAS, that were further altered when mice underwent both challenges. TBI but not BCAS increased mitochondrial oxidative metabolism. Both BCAS and TBI decreased cerebrovascular responses to repeated whisker stimulation. BCAS induced oxidative damage and inflammation in the vasculature as well as loss of vascular density, and reduced the numbers of angiogenic tip cells. Finally, intravascular protein accumulation was increased among mice that experienced both BCAS and TBI. Overall, our findings reveal that a prior vascular impairment significantly alters the profile of vascular health and function of the cerebrovasculature, and when combined with TBI may result in worsened outcomes.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}