Experimental Neurology最新文献

{"title":"GSK-3β inhibitor amplifies autophagy-lysosomal pathways by regulating TFEB in Parkinson's disease models","authors":"Jiahong Zhong ,&nbsp;Xihui Yu ,&nbsp;Yunming Zhong ,&nbsp;Liya Tan ,&nbsp;Fayou Yang ,&nbsp;Jialan Xu ,&nbsp;Jianlin Wu ,&nbsp;Zhuomiao Lin","doi":"10.1016/j.expneurol.2024.115033","DOIUrl":"10.1016/j.expneurol.2024.115033","url":null,"abstract":"<div><div>Parkinson's disease (PD), a common neurodegenerative disorder characterized by degeneration of the substantia nigra and a marked increase in Lewy bodies in the brain, primarily manifests as motor dysfunction. Glycogen synthase kinase-3 beta (GSK-3β) is known to play a critical role in various pathological processes of neurodegenerative diseases. However, the impact of GSK-3β inhibitors on PD progression and the underlying molecular mechanisms responsible for the effects have not been fully elucidated. Using in vitro and mouse models of 1-methyl-4-phenylpyridine (MPP⁺)-or methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD, we found that inhibition of GSK-3β activity alleviated mitochondrial damage, cell apoptosis, and neuronal cell loss by promoting the nuclear translocation of transcription factor EB (TFEB), thereby amplifying the autophagy-lysosomal pathway (ALP). Importantly, siRNA silencing of the TFEB gene impaired the GSK-3β inhibitor-mediated activation of the ALP pathway, thus negating the metabolic support required for neuronal functional improvement. Short-term treatment with the GSK-3β inhibitor significantly ameliorated motor dysfunction and improved motor coordination in model mice with MPTP-induced PD. GSK-3β inhibition increased the ALP and TFEB activities in the mice, thereby reducing α-synuclein aggregation and neuronal damage. In conclusion, our study demonstrates that inhibition of GSK-3β activity can delay the pathological processes of PD via promotion of the TFEB–ALP pathway, potentially providing a novel therapeutic target for this neurodegenerative disorder.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115033"},"PeriodicalIF":4.6,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566807","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":"TREM1 induces microglial ferroptosis through the PERK pathway in diabetic-associated cognitive impairment","authors":"Yujing Zhao ,&nbsp;Hongyan Guo ,&nbsp;Qiao Li ,&nbsp;Nan Wang ,&nbsp;Chaoying Yan ,&nbsp;Simei Zhang ,&nbsp;Yicong Dong ,&nbsp;Chang Liu ,&nbsp;Wei Gao ,&nbsp;Yaomin Zhu ,&nbsp;Qing Li","doi":"10.1016/j.expneurol.2024.115031","DOIUrl":"10.1016/j.expneurol.2024.115031","url":null,"abstract":"<div><div>Ferroptosis is involved in neurodegenerative disorders including diabetes-associated cognitive impairment (DACI). As central immune cells, microglia have strong siderophilic properties. However, the role of iron deposition in microglia and the underlying regulatory mechanism remains unclear in DACI. Here, we established high glucose (HG) model in BV2/HMC3 cells and diabetes model in C57BL/6 J mice with HFD and STZ. Transmission Electron Microscopy, Western blot, assay kits of Fe²⁺, GSH/GSSG, MDA and ROS were carried out <em>in vitro</em>. Prussian blue staining, Western blot and immunofluorescence were implemented <em>in vivo</em>. Y-maze and novel object recognition were performed to assess cognitive performance. LP17 was used to inhibit TREM1 (triggering receptor expressed on myeloid cells 1) specifically <em>in vivo and vitro</em>. We found excessively deposited iron and significant reduction in antioxidants in hippocampal microglia of mice with DACI, concomitant with increased TREM1 (a microglia-specific inflammatory amplifier). Furthermore, LP17 (TREM1 specific inhibitor) ameliorated cognitive impairment caused by HFD/STZ through relieving iron accumulation and antioxidant inactivation. <em>In vitro</em>, ferroptosis was induced by HG in mice microglia-BV2 and human microglia-HMC3 cells, which could be blocked by a ferroptosis inhibitor-Fer-1 and LP17. Moreover, PERK pathway of endoplasmic reticulum stress was activated by HG, and then reversed by PERK inhibitor GSK2606414 and LP17 followed by improved ferroptosis in HG-cultured BV2. In summary, our results indicated that TREM1 effectively aggravates T2DM-associated microglial iron accumulation through the PERK pathway of ERS, which contributes to antioxidant inactivation and lipid peroxidation, eventually, massively boosted ROS result in microglial ferroptosis. The mechanism elucidation in our study may shed light on targeted therapy of DACI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115031"},"PeriodicalIF":4.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497765","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":"Rotating magnetic field improves cognitive and memory impairments in APP/PS1 mice by activating autophagy and inhibiting the PI3K/AKT/mTOR signaling pathway","authors":"Mengqing Li ,&nbsp;Yaxian Mo ,&nbsp;Qinyao Yu ,&nbsp;Umer Anayyat ,&nbsp;Hua Yang ,&nbsp;Fen Zhang ,&nbsp;Yunpeng Wei ,&nbsp;Xiaomei Wang","doi":"10.1016/j.expneurol.2024.115029","DOIUrl":"10.1016/j.expneurol.2024.115029","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a geriatric disorder that can be roughly classified into sporadic AD and hereditary AD. The latter is strongly associated with genetic factors, and its treatment poses greater challenges compared to sporadic AD. Rotating magnetic fields (RMF) is a non-invasive treatment known to have diverse biological effects, including the modulation of the central nervous system and aging. However, the impact of RMF on hereditary AD and its underlying mechanism remain unexplored. In this study, we exposed APP/PS1 mice to RMF (2 h/day, 0.2 T, 4 Hz) for a duration of 6 months. The results demonstrated that RMF treatment significantly ameliorated their cognitive and memory impairments, attenuated neuronal damage, and reduced amyloid deposition. Furthermore, RNA-sequencing analysis revealed a significant enrichment of autophagy-related genes and the PI3K/AKT-mTOR signaling pathway. Western blotting further confirmed that RMF activated autophagy and suppressed the phosphorylation of proteins associated with the PI3K/AKT/mTOR signaling pathway in APP/PS1 mice. These protective effects and the underlying mechanism were also observed in Aβ₂₅_–₃₅-exposed HT22 cells. Collectively, our findings indicate that RMF improves cognitive and memory dysfunction in APP/PS1 mice by activating autophagy and inhibiting the PI3K/AKT/mTOR signaling pathway, thus highlighting the potential of RMF as a clinical treatment for hereditary AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115029"},"PeriodicalIF":4.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497763","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":"Combination treatment with cilostazol and isosorbide mononitrate attenuates microemboli-mediated vascular cognitive impairment and improves imaging and plasma biomarkers in diabetic rats","authors":"Weiguo Li ,&nbsp;Alice A. Li ,&nbsp;Xingju Nie ,&nbsp;Joshua Voltin ,&nbsp;Lianying He ,&nbsp;Eda Karakaya ,&nbsp;Jazlyn Edwards ,&nbsp;Sarah Jamil ,&nbsp;Kareem Abdelsaid ,&nbsp;Maria Fatima Falangola ,&nbsp;Adviye Ergul","doi":"10.1016/j.expneurol.2024.115030","DOIUrl":"10.1016/j.expneurol.2024.115030","url":null,"abstract":"<div><div>Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment &amp; dementia (VCID). Given the cerebrovascular dysfunction is a mutual pathological change between diabetes and VCID, we hypothesized that the cognitive impairment in this ME model can be prevented by improving the endothelial function in diabetes. Our treatment paradigm was based on the LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (Cil) treatments in small vessel disease progression. Control and diabetic rats were treated with ISMN/Cil or vehicle for 4 weeks, then injected with cholesterol crystal ME and the behavioral outcomes were monitored. Brain microstructure integrity was assessed by diffusion MRI. Plasma biomarkers were assessed using angiogenesis, neurology and amyloid β 42/40 panels recommended by the MarkVCID consortium. Behavioral deficits and the loss of tissue integrity previously observed in untreated diabetic rats were not noted in the treated animals in this study. Treatment improved tissue perfusion but there were no differences in plasma biomarkers. These results suggest that restoration of endothelial function with ISMN/Cil before ME injection prevented the possible deleterious effects of ME in diabetic rats by improving the endothelial integrity and it is a practical preventive and therapeutic strategy for VCID.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115030"},"PeriodicalIF":4.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554999","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":"Border-associated macrophages: From physiology to therapeutic targets in Alzheimer's disease","authors":"Fangxue Zheng ,&nbsp;Taiwei Dong ,&nbsp;Yi Chen ,&nbsp;Lang Wang ,&nbsp;Guoping Peng","doi":"10.1016/j.expneurol.2024.115021","DOIUrl":"10.1016/j.expneurol.2024.115021","url":null,"abstract":"<div><div>Border-associated macrophages (BAMs) constitute a highly heterogeneous group of central nervous system-resident macrophages at the brain boundaries. Despite their significance, BAMs have mainly been overlooked compared to microglia, resulting in a limited understanding of their functions. However, recent advancements in single-cell immunophenotyping and transcriptomic analyses of BAMs have revealed a previously unrecognized complexity in these cells, in addition to their critical roles under non-pathological conditions and diseases like Alzheimer's disease (AD), Parkinson's disease, glioma, and ischemic stroke. In this review, we discuss the origins, self-renewal capabilities, and extensive heterogeneity of BAMs, and clarify their important physiological functions such as immune monitoring, waste removal and vascular permeability regulation. We also summarize experimental evidence linking BAMs to the progression of AD. Finally, we review therapeutic strategies targeting brain innate immune cells mainly focusing on strategies aimed at modulating BAMs to treat AD and evaluate their potential in clinical applications.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115021"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497760","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":"Effect of vildagliptin conjugated monometallic nanoparticles and bimetallic nanocomposites on diabetes-induced cognitive deficit","authors":"Sweta Priyadarshini Pradhan ,&nbsp;Anindita Behera ,&nbsp;Pratap Kumar Sahu","doi":"10.1016/j.expneurol.2024.115026","DOIUrl":"10.1016/j.expneurol.2024.115026","url":null,"abstract":"<div><div>Oxidative stress is one of the major causes of different metabolic disorders, including diabetes, cardiovascular diseases, neurodegenerative diseases and cancers. Some metabolic disorders like diabetes mellitus leads to secondary complications after micro and macrovascular complications. Some of the most prevalent neurodegenerative diseases, like cognitive impairment and Alzheimer's disease, are found in chronic diabetic patients. The present study is designed to understand the mechanism of interconnection between diabetes mellitus and cognitive deficit using the alloxan model of diabetes-induced cognitive deficit in the rat model. The alloxan monohydrate produces reactive oxygen species, producing superoxide free radicals, hydrogen peroxide and hydroxyl radicals. The hydroxyl radicals ultimately cause the death of beta cells, causing diabetes. Hence, the correlation of oxidative stress and neurodegeneration in cognitive impairment is the trigger for this study. In the present study, we investigate the ameliorative effect of vildagliptin (VLD) and its conjugated nanoparticles against alloxan-associated brain damage due to oxidative stress. The gold (Au), selenium (Se) nanoparticles, and bimetallic (Se@Au) nanocomposites of VLD are synthesized and assessed for improvement in their brain availability. The in-vitro antioxidant evaluation of the VLD and nanoparticles is done using DPPH, ABTS, and FRAP assay. The memory-related neurobehavioral studies, in-vivo antioxidant studies, in-vivo biochemical studies, and histopathological examinations are evaluated in rat brains. The VLD and its nanoformulations exhibited in-vitro and in-vivo antioxidant properties significantly (<em>p</em> &lt; 0.01). They reduced the activity of AChE and nitrite in the alloxan diabetic rats. The bimetallic Se@Au VLDNCs displayed a more protective effect than VLD, VLD–AuNPs, and VLD–SeNPs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115026"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497761","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":"Targeting PTEN in ischemic stroke: From molecular mechanisms to therapeutic potentials","authors":"Yane Zheng ,&nbsp;Huiying Gu ,&nbsp;Yuming Kong","doi":"10.1016/j.expneurol.2024.115023","DOIUrl":"10.1016/j.expneurol.2024.115023","url":null,"abstract":"<div><div>Ischemic stroke remains a leading cause of mortality and disability worldwide, driven by complex pathophysiological mechanisms, including excitotoxicity, oxidative stress, apoptosis, and neuroinflammation. PTEN (Phosphatase and tensin homolog deleted on chromosome 10) plays a crucial role in these processes, influencing key signaling pathways such as PI3K/Akt and mTOR. This review aims to explore PTEN's multifaceted functions in ischemic stroke, examining its interactions with non-coding RNAs, involvement in mitophagy and immune suppression, and overall impact on cellular homeostasis. We will investigate various therapeutic strategies targeting PTEN, including synthetic drugs, natural products, and exosome-based therapies enriched with specific miRNAs. Additionally, we will assess the potential of non-pharmaceutical interventions such as electroacupuncture, exercise, transcranial direct current stimulation (tDCS), and therapeutic hypothermia in modulating PTEN activity to enhance cererbroprotection and functional recovery. By elucidating these aspects, this review aims to inspire and motivate the audience in their research and clinical practice, highlighting PTEN as a promising therapeutic target and paving the way for developing effective treatments for ischemic stroke.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115023"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497764","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 variant of the Hspa8 synaptic chaperone modifies disease in a SOD1G86R mouse model of amyotrophic lateral sclerosis","authors":"Taishi Takeda ,&nbsp;Yoon-Ra Her ,&nbsp;Jeong-Ki Kim ,&nbsp;Narendra N. Jha ,&nbsp;Umrao R. Monani","doi":"10.1016/j.expneurol.2024.115024","DOIUrl":"10.1016/j.expneurol.2024.115024","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8^G470R in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115024"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497759","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":"Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S","authors":"Sara M. Ricardez Hernandez ,&nbsp;Bassil Ahmed ,&nbsp;Yaser Al Rawi ,&nbsp;F. Javier Llorente Torres ,&nbsp;Mona O. Garro Kacher ,&nbsp;Catherine L. Smith ,&nbsp;Zayd Al Rawi ,&nbsp;Jessica Garcia ,&nbsp;Nicole L. Nichols ,&nbsp;Christian L. Lorson ,&nbsp;Monique A. Lorson","doi":"10.1016/j.expneurol.2024.115025","DOIUrl":"10.1016/j.expneurol.2024.115025","url":null,"abstract":"<div><div>Mutations in the Immunoglobulin mu DNA binding protein 2 (<em>IGHMBP2</em>) gene result in two distinct diseases, SMA with Respiratory Distress Type I (SMARD1) and Charcot Marie Tooth Type 2S (CMT2S). To understand the phenotypic and molecular differences between SMARD1 and CMT2S, and the role of IGHMBP2 in disease development, we generated mouse models based on six <em>IGHMBP2</em> patient mutations. Previously, we reported the development and characterization of <em>Ighmbp2</em>^D564N/D564N mice and in this manuscript, we examine two mutations: D565N (D564N in mice) and H924Y (H922Y in mice) in the <em>Ighmbp2</em>^H922Y/H922Y and <em>Ighmbp2</em>^D564N/H922Y contexts. We found significant differences between these mouse models, providing critical insight into the role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S. Importantly, these studies also demonstrate how disease pathogenesis is significantly altered in the context of <em>Ighmbp2</em> D564N and H922Y homozygous recessive and compound heterozygous mutations. Notably, there were short-lived and long-lived lifespan cohorts within <em>Ighmbp2</em>^D564N/H922Y mice with early (P12/P16) respiratory pathology serving as a key predictor of lifespan. Despite differences in lifespan, motor function deficits initiated early and progressively worsened in all <em>Ighmbp2</em>^D564N/H922Y mice. There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in <em>Ighmbp2</em>^D564N/H922Y mice. Consistent with CMT2S, <em>Ighmbp2</em>^H922Y/H922Y mice did not have altered lifespans nor respiratory pathology. Interestingly, <em>Ighmbp2</em>^H922Y/H922Y limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180. This is the first study that demonstrates differences associated with IGHMBP2 function within respiration with those within limb motor function. Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these <em>IGHMBP2</em> patient mutations and IGHMBP2 biochemical activity. Importantly, these studies reveal the dynamic differences that are presented when either a single mutant protein is present (IGHMBP2-D564N or IGHMBP2-H922Y) or two mutant proteins are present (IGHMBP2-D564N and IGHMBP2-H922Y) within cells.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115025"},"PeriodicalIF":4.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497762","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":"Theta-burst transcranial magnetic stimulation attenuates chronic ischemic demyelination and vascular cognitive impairment in mice","authors":"Di Wang ,&nbsp;Xiaohao Zhang ,&nbsp;Zhenqian Huang ,&nbsp;Yunzi Li ,&nbsp;Xinyi Wang ,&nbsp;Jia Wang ,&nbsp;Ying Zhao ,&nbsp;Qiushi Lv ,&nbsp;Min Wu ,&nbsp;Mingming Zha ,&nbsp;Kang Yuan ,&nbsp;Wusheng Zhu ,&nbsp;Gelin Xu ,&nbsp;Yi Xie","doi":"10.1016/j.expneurol.2024.115022","DOIUrl":"10.1016/j.expneurol.2024.115022","url":null,"abstract":"<div><div>Vascular cognitive impairment and dementia (VCID) is mainly caused by chronic cerebral hypoperfusion and subsequent white matter lesions. Noninvasive transcranial magnetic stimulation has been utilized in treating various neurological disorders. However, the function of theta-burst transcranial magnetic stimulation on VCID remains to be defined. We utilized 4-week bilateral carotid artery stenosis model of male mice to mimic VCID. Intermittent theta-burst stimulation (iTBS) or consecutive theta-burst stimulation (cTBS) was administered for 14 consecutive days. Through luxol fast blue staining, electron microscopy and immunofluorescence, we found that iTBS, not cTBS, significantly improved demyelination, axonal damage and β-amyloid deposition, without affecting cerebral blood flow in VCID mice. At cellular levels, iTBS rescued the loss of mature oligodendrocytes, promoted precursor cell differentiation, and inhibited pro-inflammatory activation of astrocytes and microglia. Notably, iTBS attenuated cognitive deterioration in both short-term retention and long-term spatial memory of VCID mice as indicated by serial neurobehavioral tests. To explore the molecular involvement of iTBS, mRNA sequencing was carried out. By real-time PCR and combined RNA fluorescence in situ hybridization with immunofluorescence, iTBS was confirmed to increase <em>Rxrg</em> expression specifically in mature oligodendrocytes. Collectively, iTBS could ameliorate vascular cognitive dysfunction, probably via mitigating white matter lesions and neuroinflammation in the corpus callosum. <em>Rxrg</em> signaling in mature oligodendrocytes, which was increased by iTBS, might be a potential target for VCID treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"383 ","pages":"Article 115022"},"PeriodicalIF":4.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497766","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}