Experimental Neurology最新文献

{"title":"Validation of optimised intracranial spectroscopic probe for instantaneous in-situ monitoring and classification of traumatic brain injury","authors":"Clarissa A. Stickland ,&nbsp;Zoltan Sztranyovszky ,&nbsp;Jonathan J.S. Rickard ,&nbsp;Pola Goldberg Oppenheimer","doi":"10.1016/j.expneurol.2024.114960","DOIUrl":"10.1016/j.expneurol.2024.114960","url":null,"abstract":"<div><div>The development of an optical interface to directly distinguish the brain tissue's biochemistry is the next step in understanding traumatic brain injury (TBI) pathophysiology and the best and most appropriate treatment in cases where in-hospital intracranial access is required. Despite TBI being a globally leading cause of morbidity and mortality in patients under 40, there is still a lack of objective diagnostical tools. Further, given its pathophysiological complexity the majority of treatments provided are purely symptomatic without standardized therapeutic targets. Our tailor-engineered prototype of the intracranial Raman spectroscopy probe (Intra-RSP) is designed to bridge the gap and provide real-time spectroscopic insights to monitor TBI and its evolution as well as identify patient-specific molecular targets for timely intervention. Raman spectroscopy being rapid, label-free and non-destructive, renders it an ideal portable diagnostics tool. In combination with our in-house developed software, using machine learning algorithms for multivariate analysis, the Intra-RSP is shown to accurately differentiate simulated TBI conditions in rat brains from the healthy controls, directly from the brain surface as well as through the rat's skull. Using clinically pre-established methods of cranial entry, the Intra-RSP can be inserted into a 2-piece optimised cranial bolt with integrated focussing and correctly identify a sample in real-life conditions with an accuracy &gt;80 %. To further validate the Intra-RSP's efficiency as a TBI monitoring device, rat brains mildly damaged from inflicted spinal cord injury were found to be correctly classified with 94.5 % accuracy. Through optimization and rigorous <em>in-vivo</em> validation, the Intra-RSP prototype is envisioned to seamlessly integrate into existing standards of neurological care, serving as a minimally invasive<em>, in-situ</em> neuromonitoring tool. This transformative approach has the potential to revolutionize the landscape of neurological care by providing clinicians with unprecedented insights into the nature of brain injuries and fostering targeted, timely and effective therapeutic interventions.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114960"},"PeriodicalIF":4.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002863/pdfft?md5=43d210ba9d5f05cf6e79a8469696414e&pid=1-s2.0-S0014488624002863-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282667","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":"Dendritic morphological development of traumatic brain injury-induced new neurons in the dentate gyrus is important for post-injury cognitive recovery and is regulated by Notch1","authors":"Nicole M. Weston,&nbsp;Jakob C. Green,&nbsp;Timothy N. Keoprasert,&nbsp;Dong Sun","doi":"10.1016/j.expneurol.2024.114963","DOIUrl":"10.1016/j.expneurol.2024.114963","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a prevalent problem with survivors suffering from chronic cognitive impairments. Following TBI there is a series of neuropathological changes including neurogenesis. It is well established that neurogenesis in the dentate gyrus (DG) of the hippocampus is important for hippocampal dependent learning and memory functions. Following TBI, injury-enhanced hippocampal neurogenesis is believed to contribute to post-injury cognitive recovery. Behavioral function is connected to synaptic plasticity and neuronal dendritic branching is critical for successful synapse formation. To ascertain the functional contribution of injury-induced DG new neurons in post-TBI cognitive recovery, it is necessary to study their dendritic morphological development and the molecular mechanisms controlling this process. Utilizing transgenic mice with tamoxifen-induced GFP expression and Notch1 knock-out in nestin+ neural stem cells, this study examined dendritic morphology, the role of Notch1 in regulating dendritic complexity of injury-induced DG new neurons, and their association to post-TBI cognitive recovery. We found that at 8 weeks after a moderate TBI, injury-induced DG new neurons in the injured control mice displayed a similar dendritic morphology as the cells in non-injured mice accompanied with cognitive recovery. In comparison, in Notch1 conditional knock-out mice, DG new neurons in the injured mice had a significant reduction in dendritic morphological development including dendritic arbors, volume span, and number of branches in comparison to the cells in non-injured mice concomitant with persistent cognitive dysfunction. The results of this study confirm the importance of post-injury generated new neurons in cognitive recovery following TBI and the role of Notch1 in regulating their maturation process.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114963"},"PeriodicalIF":4.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282665","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":"A new strategy for the treatment of intracerebral hemorrhage: Ferroptosis","authors":"Ke Yao Sun ,&nbsp;Xin Yue Bai ,&nbsp;Lei Zhang ,&nbsp;Xin Zhang ,&nbsp;Qian Qian Hu ,&nbsp;Yu Xuan Song ,&nbsp;Rong Rong Qiang ,&nbsp;Ning Zhang ,&nbsp;Jia Lun Zou ,&nbsp;Yan Ling Yang ,&nbsp;Yang Xiang","doi":"10.1016/j.expneurol.2024.114961","DOIUrl":"10.1016/j.expneurol.2024.114961","url":null,"abstract":"<div><p>Intracerebral hemorrhage, is a cerebrovascular disease with high morbidity, mortality, and disability. Due to the lack of effective clinical treatments, the development of new drugs to treat intracerebral hemorrhage is necessary. In recent years, ferroptosis has been found to play an important role in the pathophysiological process of intracerebral hemorrhage, which can be treated by inhibiting ferroptosis and thus intracerebral hemorrhage. This article aims to explain the mechanism of ferroptosis and its relationship to intracerebral hemorrhage. In the meantime, it briefly discusses the molecules identified to alleviate intracerebral hemorrhage by inhibiting ferroptosis, along with other clinical agents that are expected to treat intracerebral hemorrhage through this mechanism. In addition, a brief overview of the morphological alterations of different forms of cell death and their role in ICH is provided. Finally, the challenges that may arise in translating ferroptosis inhibitors from basic research to clinical use are presented. This article serves as a reference and provides insights to aid in the treatment of intracerebral hemorrhage in the clinic.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114961"},"PeriodicalIF":4.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239076","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":"Gas6/Axl signaling promotes hematoma resolution and motivates protective microglial responses after intracerebral hemorrhage in mice","authors":"Xiang-Hua Ye ,&nbsp;Zhi-Ming Xu ,&nbsp;Dan Shen ,&nbsp;Yu-Jia Jin ,&nbsp;Jia-Wen Li ,&nbsp;Xu-Hua Xu ,&nbsp;Lu-Sha Tong ,&nbsp;Feng Gao","doi":"10.1016/j.expneurol.2024.114964","DOIUrl":"10.1016/j.expneurol.2024.114964","url":null,"abstract":"<div><h3>Background</h3><p>Intracerebral hemorrhage (ICH) stands out as the most fatal subtype of stroke, currently devoid of effective therapy. Recent research underscores the significance of Axl and its ligand growth arrest-specific 6 (Gas6) in normal brain function and a spectrum of neurological disorders, including ICH. This study is designed to delve into the role of Gas6/Axl signaling in facilitating hematoma clearance and neuroinflammation resolution following ICH.</p></div><div><h3>Methods</h3><p>Adult male C57BL/6 mice were randomly assigned to sham and ICH groups. ICH was induced by intrastriatal injection of autologous arterial blood. Recombinant mouse Gas6 (rmGas6) was administered intracerebroventricularly 30 min after ICH. Virus-induced knockdown of Axl or R428 (a selective inhibitor of Axl) treatment was administrated before ICH induction to investigate the protective mechanisms. Molecular changes were assessed using western blot, enzyme-linked immunosorbent assay and immunohistochemistry. Coronal brain slices, brain water content and neurobehavioral tests were employed to evaluate histological and neurofunctional outcomes, respectively. Primary glia cultures and erythrophagocytosis assays were applied for mechanistic studies.</p></div><div><h3>Results</h3><p>The expression of Axl increased at 12 h after ICH, peaking on day 3. Gas6 expression did not remarkably changed until day 3 post-ICH. Early administration of rmGas6 following ICH significantly reduced hematoma volume, mitigated brain edema, and restored neurological function. Both Axl-knockdown and Axl inhibitor treatment abolished the neuroprotection of exogenous Gas6 in ICH. In vitro studies demonstrated that microglia exhibited higher capacity for phagocytosing eryptotic erythrocytes compared to normal erythrocytes, a process reversed by blocking the externalized phosphatidylserine on eryptotic erythrocytes. The erythrophagocytosis by microglia was Axl-mediated and Gas6-dependent. Augmentation of Gas6/Axl signaling attenuated neuroinflammation and drove microglia towards pro-resolving phenotype.</p></div><div><h3>Conclusions</h3><p>This study demonstrated the beneficial effects of recombinant Gas6 on hematoma resolution, alleviation of neuroinflammation, and neurofunctional recovery in an animal model of ICH. These effects were primarily mediated by the phagocytotic role of Axl expressed on microglia.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114964"},"PeriodicalIF":4.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239090","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":"Viral overexpression of human alpha-synuclein in mouse substantia nigra dopamine neurons results in hyperdopaminergia but no neurodegeneration","authors":"Sofia Ines Garcia Moreno ,&nbsp;Fabian Limani ,&nbsp;Iina Ludwig ,&nbsp;Catherine Gilbert ,&nbsp;Christian Pifl ,&nbsp;Thomas S. Hnasko ,&nbsp;Thomas Steinkellner","doi":"10.1016/j.expneurol.2024.114959","DOIUrl":"10.1016/j.expneurol.2024.114959","url":null,"abstract":"<div><p>Loss of select neuronal populations such as midbrain dopamine (DA) neurons is a pathological hallmark of Parkinson's disease (PD). The small neuronal protein α-synuclein has been related both genetically and neuropathologically to PD, yet how and if it contributes to selective vulnerability remains elusive. Here, we describe the generation of a novel adeno-associated viral vector (AAV) for Cre-dependent overexpression of wild-type human α-synuclein. Our strategy allows us to restrict α-synuclein to select neuronal populations and hence investigate the cell-autonomous effects of elevated α-synuclein in genetically-defined cell types. Since DA neurons in the substantia nigra <em>pars compacta</em> (SNc) are particularly vulnerable in PD, we investigated in more detail the effects of increased α-synuclein in these cells. AAV-mediated overexpression of wildtype human α-synuclein in SNc DA neurons increased the levels of α-synuclein within these cells and augmented phosphorylation of α-synuclein at serine-129, which is considered a pathological feature of PD and other synucleinopathies. However, despite abundant α-synuclein overexpression and hyperphosphorylation we did not observe any dopaminergic neurodegeneration up to 90 days post virus infusion. In contrast, we noticed that overexpression of α-synuclein resulted in increased locomotor activity and elevated striatal DA levels suggesting that α-synuclein enhanced dopaminergic activity. We therefore conclude that cell-autonomous effects of elevated α-synuclein are not sufficient to trigger acute dopaminergic neurodegeneration.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114959"},"PeriodicalIF":4.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002851/pdfft?md5=c15dd07b0c0336700c1efe393d75bdba&pid=1-s2.0-S0014488624002851-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239089","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":"A comparison of the antiepileptogenic efficacy of two rationally chosen multitargeted drug combinations in a rat model of posttraumatic epilepsy","authors":"Mustafa Q. Hameed ,&nbsp;Raimondo D’Ambrosio ,&nbsp;Cliff Eastman ,&nbsp;Benjamin Hui ,&nbsp;Rui Lin ,&nbsp;Sheryl Anne D. Vermudez ,&nbsp;Amanda Liebhardt ,&nbsp;Yongho Choe ,&nbsp;Pavel Klein ,&nbsp;Chris Rundfeldt ,&nbsp;Wolfgang Löscher ,&nbsp;Alexander Rotenberg","doi":"10.1016/j.expneurol.2024.114962","DOIUrl":"10.1016/j.expneurol.2024.114962","url":null,"abstract":"<div><p>Post-traumatic epilepsy (PTE) is a recurrent and often drug-refractory seizure disorder caused by traumatic brain injury (TBI). No single drug treatment prevents PTE, but preventive drug combinations that may prophylax against PTE have not been studied. Based on a systematic evaluation of rationally chosen drug combinations in the intrahippocampal kainate (IHK) mouse model of acquired epilepsy, we identified two multi-targeted drug cocktails that exert strong antiepileptogenic effects. The first, a combination of levetiracetam (LEV) and topiramate, only partially prevented spontaneous recurrent seizures in the model. We therefore added atorvastatin (ATV) to the therapeutic cocktail (TC) to increase efficacy, forming “TC-001”. The second cocktail – a combination of LEV, ATV, and ceftriaxone, termed “TC-002” – completely prevented epilepsy in the mouse IHK model. In the present proof-of-concept study, we tested whether the two drug cocktails prevent epilepsy in a rat PTE model in which recurrent electrographic seizures develop after severe rostral parasagittal fluid percussion injury (FPI). Following FPI, rats were either treated over 3–4 weeks with vehicle or drug cocktails, starting either 1 or 4–6 h after the injury. Using mouse doses of TC-001 and TC-002, no significant antiepileptogenic effect was obtained in the rat PTE model. However, when using allometric scaling of drug doses to consider the differences in body surface area between mice and rats, PTE was prevented by TC-002. Furthermore, the latter drug cocktail partially prevented the loss of perilesional cortical parvalbumin-positive GABAergic interneurons. Plasma and brain drug analysis showed that these effects of TC-002 occurred at clinically relevant levels of the individual TC-002 drug components. In silico analysis of drug-drug brain protein interactions by the STITCH database indicated that TC-002 impacts a larger functional network of epilepsy-relevant brain proteins than each drug alone, providing a potential network pharmacology explanation for the observed antiepileptogenic and neuroprotective effects observed with this combination.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114962"},"PeriodicalIF":4.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002887/pdfft?md5=e82c1a573703b24dc3fa46664d30f914&pid=1-s2.0-S0014488624002887-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258633","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":"Phloretin alleviates sleep deprivation-induced cognitive impairment by reducing inflammation through PPARγ/NF-κB signaling pathway","authors":"Wenjun Chen ,&nbsp;Mei Liu ,&nbsp;Ziming Li ,&nbsp;Zhoucai Luo ,&nbsp;Jianlin Wu","doi":"10.1016/j.expneurol.2024.114949","DOIUrl":"10.1016/j.expneurol.2024.114949","url":null,"abstract":"<div><p>Sleep loss leads to significant pathophysiological consequences, including cognitive impairment. The neuroinflammation are pivotal factors in the pathogenesis of cognitive impairment induced by sleep loss. The phloretin (PHL), derived from peel of juicy fruits, has demonstrated potent anti-inflammatory properties. However, the precise influence of PHL on the cognitive impairment triggered by sleep loss and its underlying mechanism remain uncertain. In the present study, mice were subjected to sleep deprivation (SD) paradigm. Cognitive impairment induced by SD were significantly relieved by administration of PHL in a dose-dependent manner. Furthermore, PHL not only mitigated the synaptic losses but also enhanced dendritic spine density and neuronal activity within mice hippocampus following exposure to SD. Moreover, PHL treatment decreased the microglial numbers and altered microglial morphology in the hippocampus to restore the M1/M2 balances; these effects were accompanied by regulation of pro−/anti-inflammatory cytokine production and secretion in SD-exposed mice. Additionally, in vivo and in vitro studies showed PHL might attenuate the inflammation through the PPARγ/NF-κB pathway. Our findings suggest that PHL exerts inhibitory effects on microglia-mediated neuroinflammation, thereby providing protection against cognitive impairment induced by SD through a PPAR-γ dependent mechanism. The results indicate PHL is expected to provide a valuable candidate for new drug development for SD-induced cognitive impairment in the future.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114949"},"PeriodicalIF":4.6,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239077","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":"Acute nicotine exposure attenuates neurological deficits, ischemic injury and brain inflammatory responses and restores hippocampal long-term potentiation in ischemic stroke followed by lipopolysaccharide-induced sepsis-like state","authors":"Sonia Abbaspour ,&nbsp;Javad Fahanik-Babaei ,&nbsp;Soheila Adeli ,&nbsp;Dirk M. Hermann ,&nbsp;Maryam Sardari","doi":"10.1016/j.expneurol.2024.114946","DOIUrl":"10.1016/j.expneurol.2024.114946","url":null,"abstract":"<div><p>Ischemic stroke is followed by an increased susceptibility to bacterial infections, which exacerbate histological stroke outcome, neurological deficits and memory impairment due to increased neuroinflammation and neurotransmitter dysfunction. Pharmacological activation of nicotinic acetylcholine receptors was suggested to mitigate brain inflammatory responses in ischemic stroke. The functional responses associated with nicotinic acetylcholine receptor activation were unknown. In this study, male NMRI mice subjected to transient intraluminal middle cerebral artery occlusion (MCAO) were intraperitoneally exposed to vehicle treatment or <em>Escherichia coli</em> lipopolysaccharide (LPS; 4 mg/kg)-induced sepsis-like state 24 h post-MCAO, followed by intraperitoneal administration of vehicle or nicotine (0.5 mg/kg) 30 min later. Over 96 h, rectal temperature, neurological deficits, spontaneous locomotor activity, working memory, ischemic injury, synaptic plasticity, and brain inflammatory responses were evaluated by temperature measurement, behavioral analysis, infarct volumetry, electrophysiological recordings, and polymerase-chain reaction analysis. LPS-induced sepsis induced hypothermia, increased general and focal neurological deficits, reduced spontaneous exploration behavior, reduced working memory, and increased infarct volume post-MCAO. Additional treatment with nicotine attenuated LPS-induced hypothermia, reduced neurological deficits, restored exploration behavior, restored working memory, and reduced infarct volume. Local field potential recordings revealed that LPS-induced sepsis decreased long-term potentiation (LTP) in the dentate gyrus post-MCAO, whereas concomitant nicotine exposure restored LTP in the contralateral dentate gyrus. LPS-induced sepsis increased microglial/ macrophage <em>Iba-1</em> mRNA and astrocytic <em>GFAP</em> mRNA levels post-MCAO, whereas add-on nicotine treatment reduced astrocytic <em>GFAP</em> mRNA. Taken together, these findings indicate that acute nicotine exposure enhances functional stroke recovery. Future studies will have to evaluate the effects of (1) chronic nicotine exposure, a clinically relevant vascular risk factor, and (2) the cessation of nicotine exposure, which is widely recommended post-stroke, but might have detrimental effects in the early stroke recovery phase.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114946"},"PeriodicalIF":4.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002723/pdfft?md5=e8fe160ec641e039b4b87af73cf4827a&pid=1-s2.0-S0014488624002723-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239085","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":"Microglial mitochondrial DNA release contributes to neuroinflammation after intracerebral hemorrhage through activating AIM2 inflammasome","authors":"Feng Gu ,&nbsp;Zongqi Wang ,&nbsp;Haojie Ding ,&nbsp;Xinyu Tao ,&nbsp;Juyi Zhang ,&nbsp;Kun Dai ,&nbsp;Xiang Li ,&nbsp;Haitao Shen ,&nbsp;Haiying Li ,&nbsp;Zhouqing Chen ,&nbsp;Zhong Wang","doi":"10.1016/j.expneurol.2024.114950","DOIUrl":"10.1016/j.expneurol.2024.114950","url":null,"abstract":"<div><p>Intracerebral hemorrhage (ICH) is a severe disease that often leads to disability and death. Neuroinflammatory response is a key causative factor of early secondary brain injury after ICH. AIM2 is a DNA-sensing protein that recognizes cytosolic double-stranded DNA and take a significant part in neuroinflammation. Mitochondrial DNA participates in the translation of proteins such as the respiratory chain in the mitochondria. Whether mtDNA is involved in forming AIM2 inflammasome after ICH remains unclear. We used mice to construct ICH model in vivo and we used BV2 microglial cells treated with oxyhemoglobin to simulate ICH in vitro. Following lentiviral transfection to overexpress AIM2 antagonist P202, a notable decrease was observed in the levels of AIM2 inflammasome-associated proteins, leading to a reduction in dead neurons surrounding the hematoma and an enhancement in long-term and short-term behavior of neurological deficits. We further explored whether mtDNA took part in the AIM2 activation after ICH. The cytosolic mtDNA level was down-regulated by the mitochondrial division protector Mdivi-1 and up-regulated by transfection of mtDNA into cytoplasm. We found the expression level of AIM2 inflammasome-related proteins and inflammatory cytokines release were regulated by the cytosolic mtDNA level. In conclusion, after ICH, the mtDNA content in the cytoplasm of microglia around the hematoma rises, causing AIM2 inflammation leading to neuronal apoptosis, which leads to neurological deficits in mice. On the other hand, P202 was able to block inflammatory vesicle activation and improve neurological function by preventing the interaction between AIM2 protein and mitochondrial DNA.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114950"},"PeriodicalIF":4.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239086","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":"CHCHD10P80L knock-in zebrafish display a mild ALS-like phenotype","authors":"Virginie Petel Légaré ,&nbsp;Ziyaan A. Harji ,&nbsp;Christian J. Rampal ,&nbsp;Hana Antonicka ,&nbsp;Tyler J.N. Gurberg ,&nbsp;Olivia Persia ,&nbsp;Esteban C. Rodríguez ,&nbsp;E.A. Shoubridge ,&nbsp;Gary A.B. Armstrong","doi":"10.1016/j.expneurol.2024.114945","DOIUrl":"10.1016/j.expneurol.2024.114945","url":null,"abstract":"<div><p>Mutations in the nuclear-encoded mitochondrial gene <em>CHCHD10</em> have been observed in patients with a spectrum of diseases that include amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathogenic nature of disease-associated variants of CHCHD10 we generated a zebrafish knock-in (KI) model expressing the orthologous ALS-associated CHCHD10^P80L variant (zebrafish: Chchd10^P83L). Larval <em>chchd10</em>^P83L/P83L fish displayed reduced Chchd10 protein expression levels, motor impairment, reduced survival and abnormal neuromuscular junctions (NMJ). These deficits were not accompanied by changes in transcripts involved in the integrated stress response (ISR), phenocopying previous findings in our knockout (<em>chchd10</em>^−/−). Adult, 11-month old <em>chchd10</em>^P83L/P83L zebrafish, displayed smaller slow- and fast-twitch muscle cell cross-sectional areas compared to wild type zebrafish muscle cells. Motoneurons in the spinal cord of <em>chchd10</em>^P83L/P83L zebrafish displayed similar cross-sectional areas to that of wild type motor neurons and significantly fewer motor neurons were observed when compared to <em>chchd2</em>^−/− adult spinal cords. Bulk RNA sequencing using whole spinal cords of 7-month old fish revealed transcriptional changes associated with neuroinflammation, apoptosis, amino acid metabolism and mt-DNA inflammatory response in our <em>chchd10</em>^P83L/P83L model. The findings presented here, suggest that the <em>CHCHD10</em>^P80L variant confers an ALS-like phenotype when expressed in zebrafish.</p></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"382 ","pages":"Article 114945"},"PeriodicalIF":4.6,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014488624002711/pdfft?md5=acebd485cd331dc0d00349d10242a947&pid=1-s2.0-S0014488624002711-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142219019","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}