Neurobiology of Disease最新文献

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Non-linear microglial, inflammatory and oligodendrocyte dynamics across stages of Alzheimer's disease 阿尔茨海默病各阶段的非线性小胶质细胞、炎症和少突胶质细胞动力学
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-08 DOI: 10.1016/j.nbd.2025.106950
Aurélien M. Badina , Kelly Ceyzériat , Quentin Amossé , Alexandre Tresh , Laurene Abjean , Léa Guénat , Emilie Vauthey , Stergios Tsartsalis , Philippe Millet , Benjamin B. Tournier
{"title":"Non-linear microglial, inflammatory and oligodendrocyte dynamics across stages of Alzheimer's disease","authors":"Aurélien M. Badina ,&nbsp;Kelly Ceyzériat ,&nbsp;Quentin Amossé ,&nbsp;Alexandre Tresh ,&nbsp;Laurene Abjean ,&nbsp;Léa Guénat ,&nbsp;Emilie Vauthey ,&nbsp;Stergios Tsartsalis ,&nbsp;Philippe Millet ,&nbsp;Benjamin B. Tournier","doi":"10.1016/j.nbd.2025.106950","DOIUrl":"10.1016/j.nbd.2025.106950","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by cognitive decline and neuropathological hallmarks including Aβ plaques and Tau tangles. Emerging evidence indicates oligodendrocyte (OL) dysfunction and demyelination also contribute to disease progression. Here, we analyzed OL markers and inflammatory gene expression in human hippocampal samples at early and late AD stages. In early AD, we observed OL and myelinating pathways downregulation, alongside microglial and astrocytic activation, as well as upregulated chemokine CCL2 and peripheral immune infiltration markers. In late stages, expression of OL-related genes and myelination pathways increase, with a higher NG2/MBP ratio, coinciding with decreased microglial coverage and peripheral immune markers. These findings indicate that early neuroinflammation may impair OL function, while attenuated immune activity in late AD allows partial OL recovery. This study provides insights into stage-specific inflammatory and myelin-related changes in AD, supporting the relevance of understanding oligodendrocyte dynamics and potential regenerative responses for future therapeutic strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106950"},"PeriodicalIF":5.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928253","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}
引用次数: 0
Glycosylation in neurodevelopment: What oncology teaches? 神经发育中的糖基化:肿瘤学教授什么?
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-08 DOI: 10.1016/j.nbd.2025.106945
Hours Camille , Gressens Pierre
{"title":"Glycosylation in neurodevelopment: What oncology teaches?","authors":"Hours Camille ,&nbsp;Gressens Pierre","doi":"10.1016/j.nbd.2025.106945","DOIUrl":"10.1016/j.nbd.2025.106945","url":null,"abstract":"<div><div>Neurodevelopment is a highly complex process, sensitive to a multitude of signaling pathways linked to molecular processes involved in neuronal development and function, metabolism, and immune functions. Key pathways include cell-cycle regulation (PI3K/Akt/mTOR, p53/PTEN), JAK-STAT, Notch, SLIT/Robo, epithelial-mesenchymal transition (EMT) and cellular homeostasis processes such as apoptosis, autophagy and hypoxia. Transcription regulation (including histone and epigenetic regulation) and immune regulation (NF-kB, Toll-like receptors (TLRs)) play a crucial role. Glycosylation abnormalities related to these molecular processes have been described in cancer. However, while cancer research and therapies have been revolutionized by the study of glycosylation, mechanistic insights and therapeutic approaches are still struggling to develop in neurodevelopmental pathologies. This study is a blueprint to unravel the key pathological pathways in neurodevelopment by highlighting the benefits of studying the associated regulatory processes of glycosylation, which have led to major advances in cancer research.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106945"},"PeriodicalIF":5.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928256","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}
引用次数: 0
Rodent and human seizures demonstrate a dynamic interplay with spreading depolarizations 啮齿动物和人类的癫痫发作表现出一种动态的相互作用与扩散的去极化
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-08 DOI: 10.1016/j.nbd.2025.106937
Jacob H. Norby , Daniel Hummel , Noah Ricks , John Rolston , Shervin Rahimpour , Rhiannon Cowan , Juha Voipio , Andrew J. Trevelyan , Elliot H. Smith , R. Ryley Parrish
{"title":"Rodent and human seizures demonstrate a dynamic interplay with spreading depolarizations","authors":"Jacob H. Norby ,&nbsp;Daniel Hummel ,&nbsp;Noah Ricks ,&nbsp;John Rolston ,&nbsp;Shervin Rahimpour ,&nbsp;Rhiannon Cowan ,&nbsp;Juha Voipio ,&nbsp;Andrew J. Trevelyan ,&nbsp;Elliot H. Smith ,&nbsp;R. Ryley Parrish","doi":"10.1016/j.nbd.2025.106937","DOIUrl":"10.1016/j.nbd.2025.106937","url":null,"abstract":"<div><div>Seizure termination has been linked to spreading depolarizations (SDs) in experimental models of epilepsy, and SDs have been suggested to protect against seizures. However, the precise mechanisms of seizure-associated SDs remain unclear. Additionally, the co-occurrence of SDs with human seizures remains debated.</div><div>In this study, we found that SDs are a prominent feature following ictal events in both human clinical recordings and in a rodent model of ictogenesis. Approximately one-third of rodent seizure-like events (SLEs) associated with SDs, while all human seizures analyzed associated with propagating infraslow shifts, indicative of SDs. In rodents, SDs clustered towards the end of ictal events, resulting in significantly shorter SLEs and delayed onset of subsequent SLEs. Interestingly, SLEs with SDs displayed significantly more low gamma activity during ictal events than SLEs that did not end in SDs. Furthermore, we found no significant correlation between [K<sup>+</sup>]<sub>o</sub> levels and the likelihood of SLEs ending in SDs, questioning the role of [K<sup>+</sup>]<sub>o</sub> in SD induction during seizures. Interestingly, the human data demonstrate clear SD propagation during seizures and show that SDs appear and propagate in multiple brain regions simultaneously with ictal events.</div><div>Collectively, these results indicate that SDs are a hallmark of ictal activity associated with seizure termination. Furthermore, these findings provide unique insight into the neuronal dynamics that promote SD induction by showing that increased low gamma activity during SLEs is more predictive of SD induction than [K<sup>+</sup>]<sub>o</sub> levels. Taken together, these findings provide rationale for further exploration of SDs to prematurely terminate life-threatening seizures.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106937"},"PeriodicalIF":5.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928254","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}
引用次数: 0
Expression of protein disulfide isomerase A3Q481K variant associated with amyotrophic lateral sclerosis triggers disease features in mice 与肌萎缩性侧索硬化症相关的蛋白二硫异构酶A3变异的表达引发小鼠的疾病特征。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-07 DOI: 10.1016/j.nbd.2025.106947
Martin Sepulveda , Francisca Martínez Traub , Patricia Ojeda , Viviana Perez , Jorge Ojeda , Jessica Mella , Rodrigo Diaz , Pablo Rozas , Matías Mansilla-Jaramillo , Amparo Zuleta , Guillermo Diaz , Bredford Kerr , Ute Woehlbier , Juan Pablo Henríquez , Danilo B. Medinas , Claudio Hetz
{"title":"Expression of protein disulfide isomerase A3Q481K variant associated with amyotrophic lateral sclerosis triggers disease features in mice","authors":"Martin Sepulveda ,&nbsp;Francisca Martínez Traub ,&nbsp;Patricia Ojeda ,&nbsp;Viviana Perez ,&nbsp;Jorge Ojeda ,&nbsp;Jessica Mella ,&nbsp;Rodrigo Diaz ,&nbsp;Pablo Rozas ,&nbsp;Matías Mansilla-Jaramillo ,&nbsp;Amparo Zuleta ,&nbsp;Guillermo Diaz ,&nbsp;Bredford Kerr ,&nbsp;Ute Woehlbier ,&nbsp;Juan Pablo Henríquez ,&nbsp;Danilo B. Medinas ,&nbsp;Claudio Hetz","doi":"10.1016/j.nbd.2025.106947","DOIUrl":"10.1016/j.nbd.2025.106947","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motoneurons and compromised proteostasis. Dysfunction of the endoplasmic reticulum (ER) has been identified as a transversal pathogenic mechanism associated with motoneurons vulnerability in ALS. Protein disulfide isomerases (PDIs) are key enzymes catalyzing protein folding at the ER that are altered in the disease, involving biochemical and genetic perturbations. In ALS cases, we previously identified variants in the gene encoding PDIA3 (also known as Grp58 or ERp57), which were associated with altered neurite outgrowth in cell culture and abnormal motoneuron connectivity in zebrafish. Here, we report the generation of transgenic mice expressing the ALS-associated PDIA3<sup>Q481K</sup> variant. Moderate PDIA3<sup>Q481K</sup> overexpression resulted in altered motor capacity accompanied by decreased motoneuron number. The adverse effects of PDIA3<sup>Q481K</sup> expression were associated with induction of ER stress in the spinal cord and subtle morphological changes in neuromuscular junctions. Our results suggest that the PDIA3<sup>Q481K</sup> variant is likely pathogenic and its overexpression in mice recapitulate some ALS features, further supporting the concept that altered proteostasis due to PDI dysfunction may predispose an individual to develop the disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106947"},"PeriodicalIF":5.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037319","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}
引用次数: 0
Gene co-expression patterns shared between chemobrain and neurodegenerative disease models in rodents 啮齿类动物化学脑和神经退行性疾病模型之间基因共表达模式的共享
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-06 DOI: 10.1016/j.nbd.2025.106944
Mohammad-Sajad Zare , Navid Abedpoor , Fatemeh Hajibabaie , Adam K. Walker
{"title":"Gene co-expression patterns shared between chemobrain and neurodegenerative disease models in rodents","authors":"Mohammad-Sajad Zare ,&nbsp;Navid Abedpoor ,&nbsp;Fatemeh Hajibabaie ,&nbsp;Adam K. Walker","doi":"10.1016/j.nbd.2025.106944","DOIUrl":"10.1016/j.nbd.2025.106944","url":null,"abstract":"<div><div>Chemotherapy-related cognitive impairment (CRCI), is a well-recognized phenomenon in cancer patients who have undergone chemotherapy but the exact molecular mechanisms underpinning CRCI remain elusive. Symptoms reported by people with CRCI resemble those experienced by people with age-related neurodegenerative disorders (ARNDDs), yet no clear connection between CRCI and ARNDDs has been reported to date. The existence of shared mechanisms between these conditions offers opportunities for repurposing drugs already approved for the treatment of ARNDDs to improve symptoms of CRCI. Given that there is no available microarray or RNA-Seq data from the brains of people who have experienced CRCI, we investigated to what extent brain gene expression perturbations from validated rodent models of CRCI induced by chemotherapy compared with validated rodent models of Alzheimer’s disease and Parkinson’s disease. We utilized multiple bioinformatic analyses, including functional enrichment, protein-protein interaction network analyses, gene ontology analyses and identification of hub genes to reveal connections between comparable gene expression perturbations observed in these conditions. Collectively 165 genes overlapped between CRCI and Parkinson’s disease and/or Alzheimer’s disease, and 15 overlapped between all three conditions. The joint genes between Alzheimer’s disease, Parkinson’s disease and CRCI demonstrate an average of 83.65% nucleotide sequence similarity to human orthologues. Gene ontology and pathway enrichment analyses suggest mechanisms involved in neural activity and inflammatory response as the key components of the studied neuropathological conditions. Accordingly, genes in which expression was comparably affected in all three condition models could be attributed to neuroinflammation, cell cycle arrest, and changes in physiological neural activity.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106944"},"PeriodicalIF":5.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931988","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}
引用次数: 0
Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology 神经免疫信号介导星形细胞核胞质破坏和与TDP-43病理相关的应激颗粒形成
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-06 DOI: 10.1016/j.nbd.2025.106939
Constance Zhou , Evelyn J. Hardin , Till S. Zimmer , Stephanie Jackvony , Daniel Barnett , Noopur Khobrekar , Elisa Giacomelli , Lorenz Studer , Adam L. Orr , Anna G. Orr
{"title":"Neuroimmune signaling mediates astrocytic nucleocytoplasmic disruptions and stress granule formation associated with TDP-43 pathology","authors":"Constance Zhou ,&nbsp;Evelyn J. Hardin ,&nbsp;Till S. Zimmer ,&nbsp;Stephanie Jackvony ,&nbsp;Daniel Barnett ,&nbsp;Noopur Khobrekar ,&nbsp;Elisa Giacomelli ,&nbsp;Lorenz Studer ,&nbsp;Adam L. Orr ,&nbsp;Anna G. Orr","doi":"10.1016/j.nbd.2025.106939","DOIUrl":"10.1016/j.nbd.2025.106939","url":null,"abstract":"<div><div>Alterations in transactivating response region DNA-binding protein 43 (TDP-43) are prevalent in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurological disorders. TDP-43 influences neuronal functions and might also affect glial cells. However, specific intracellular effects of TDP-43 alterations on glial cells and underlying mechanisms are not clear. We report that TDP-43 dysregulation in mouse and human cortical astrocytes causes nucleoporin mislocalization, nuclear envelope remodeling, and changes in nucleocytoplasmic protein transport. These effects are dependent on interleukin-1 (IL-1) receptor activity and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and are associated with the formation of cytoplasmic stress granules. Stimulation of IL-1 receptors and NF-κB signaling are necessary and sufficient to induce astrocytic stress granules and rapid nucleocytoplasmic changes, which are broadly alleviated by inhibition of the integrated stress response. These findings establish that TDP-43 alterations and neuroimmune factors can induce nucleocytoplasmic changes through NF-κB signaling, revealing mechanistic convergence of proteinopathy and neuroimmune pathways onto glial nucleocytoplasmic disruptions that may occur in diverse neurological conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106939"},"PeriodicalIF":5.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143928255","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}
引用次数: 0
Circadian disruption upon painful peripheral nerve injury in mice: Temporal effects on transcriptome in pain-regulating sensory tissues 小鼠疼痛周围神经损伤的昼夜节律中断:疼痛调节感觉组织转录组的时间效应
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-03 DOI: 10.1016/j.nbd.2025.106934
Wenjing Dai , Manqing Wen , Eija Kalso , Vinko Palada
{"title":"Circadian disruption upon painful peripheral nerve injury in mice: Temporal effects on transcriptome in pain-regulating sensory tissues","authors":"Wenjing Dai ,&nbsp;Manqing Wen ,&nbsp;Eija Kalso ,&nbsp;Vinko Palada","doi":"10.1016/j.nbd.2025.106934","DOIUrl":"10.1016/j.nbd.2025.106934","url":null,"abstract":"<div><h3>Background</h3><div>Neuropathic pain (NP) resulting from nerve damage shows diurnal fluctuation of intensity in patients, indicating circadian regulation. However, mechanisms linking NP and circadian regulation remain unclear. This study aimed to investigate time-dependent transcriptomic changes during a 24-hour period using a spared nerve injury (SNI) mouse model of NP.</div></div><div><h3>Methods</h3><div>Pain-related behaviours were assessed at baseline and on days 7, 14, and 21 after SNI and control sham surgeries in C57BL/6JRJ mice. Spinal cord (SC) and periaqueductal gray (PAG) were collected 4-hourly over 24 h upon completion of behavioural testing.</div></div><div><h3>Results</h3><div>RNA sequencing revealed 111 up- and 21 downregulated differentially expressed genes (DEGs) in the SC, and 35 up- and 33 downregulated DEGs in the PAG, across all six time points. The large majority of DEGs, 245 in the SC and 191 in the PAG, are involved in regulation of immunity. Among the top expressed genes, five DEGs in the SC, <em>Atf3</em>, <em>Anxa10</em>, <em>Gpr151</em>, <em>Cxcl10</em>, <em>Sprr1a</em>, and two DEGs in the PAG, <em>Igf2</em> and <em>Wnt6</em>, were previously reported to regulate pain. Circadian analysis using CircaCompare identified 383 SC transcripts and 261 PAG transcripts with altered rhythmicity. Variability of gene expression during circadian day was increased in the SC and decreased in the PAG from the SNI mice.</div></div><div><h3>Conclusion</h3><div>These findings suggest that NP disrupts the circadian expression of rhythmic transcripts in the SC and PAG, potentially revealing new targets for chronotherapy of NP.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106934"},"PeriodicalIF":5.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143907472","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}
引用次数: 0
Retraction Notice to “LRRK2 kinase activity mediates toxic interactions between genetic mutation and oxidative stress in a Drosophila model: Suppression by curcumin” [Neurobiology of Disease 47 (2012) 385–392] “在果蝇模型中,LRRK2激酶活性介导基因突变和氧化应激之间的毒性相互作用:姜黄素的抑制作用”[Neurobiology of Disease 47 (2012) 385-392]
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-03 DOI: 10.1016/j.nbd.2025.106930
Dejun Yang , Tianxia Li , Zhaohui Liu , Nicolas Arbez , Jianqun Yan , Timothy H. Moran , Christopher A. Ross , Wanli W. Smith
{"title":"Retraction Notice to “LRRK2 kinase activity mediates toxic interactions between genetic mutation and oxidative stress in a Drosophila model: Suppression by curcumin” [Neurobiology of Disease 47 (2012) 385–392]","authors":"Dejun Yang ,&nbsp;Tianxia Li ,&nbsp;Zhaohui Liu ,&nbsp;Nicolas Arbez ,&nbsp;Jianqun Yan ,&nbsp;Timothy H. Moran ,&nbsp;Christopher A. Ross ,&nbsp;Wanli W. Smith","doi":"10.1016/j.nbd.2025.106930","DOIUrl":"10.1016/j.nbd.2025.106930","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106930"},"PeriodicalIF":5.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922510","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}
引用次数: 0
Serotonin innervation of the subthalamic nucleus in parkinsonian monkeys 帕金森猴丘脑下核的血清素神经支配
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-02 DOI: 10.1016/j.nbd.2025.106938
C.V.L. Delmas , J. Munro , M. Bérard , T. Di Paolo , M. Morissette , M.E. Tremblay , A. Parent , M. Parent
{"title":"Serotonin innervation of the subthalamic nucleus in parkinsonian monkeys","authors":"C.V.L. Delmas ,&nbsp;J. Munro ,&nbsp;M. Bérard ,&nbsp;T. Di Paolo ,&nbsp;M. Morissette ,&nbsp;M.E. Tremblay ,&nbsp;A. Parent ,&nbsp;M. Parent","doi":"10.1016/j.nbd.2025.106938","DOIUrl":"10.1016/j.nbd.2025.106938","url":null,"abstract":"<div><div>The subthalamic nucleus (STN), the main driving force of the basal ganglia, is innervated by brainstem serotonin (5-HT) neurons with highly plastic axonal arborization. A pathologically-induced rearrangement of the ascending 5-HT projections could contribute to the disrupted firing pattern of STN neurons observed in Parkinson's disease (PD). This light and electron microscope study was designed to characterize the neuroadaptive changes of 5-HT inputs to the different functional territories of the STN in four cynomolgus monkeys (<em>Macaca fascicularis</em>) rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and four control animals. Using an unbiased stereological approach, we report a significant decrease of the density of 5-HT axon varicosities immunolabeled for the 5-HT membrane transporter (SERT), across all STN functional territories of MPTP-treated monkeys. In MPTP-treated animals, the SERT+ axon varicosities are larger than in control monkeys. In both experimental conditions they are only partially synaptic. A preserved length of 5-HT axons in the STN along with a conserved number of 5-HT neurons in the dorsal raphe nucleus is observed. Overall, our results indicate that, in parkinsonian monkeys, the 5-HT axons projecting to the STN are preserved but endowed with significantly less axon varicosities. Such neuroadaptive change could lead to a lower ambient level of 5-HT in this basal ganglia component, representing a compensatory mechanism designed to cope with the hyperexcitability of STN neurons that is known to occur in PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"211 ","pages":"Article 106938"},"PeriodicalIF":5.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921875","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}
引用次数: 0
Brain proteome changes after intracerebral hemorrhage in aged male and female mice 老年雌雄小鼠脑出血后脑蛋白质组的变化。
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-05-02 DOI: 10.1016/j.nbd.2025.106936
Sivaraman Kuppuswamy, Noah J. Watson, William Luke Ledford, Blake A. Pavri, Wenbo Zhi, Mary Gbadebo, Frederick Bonsack, Hongyan Xu, Sangeetha Sukumari-Ramesh
{"title":"Brain proteome changes after intracerebral hemorrhage in aged male and female mice","authors":"Sivaraman Kuppuswamy,&nbsp;Noah J. Watson,&nbsp;William Luke Ledford,&nbsp;Blake A. Pavri,&nbsp;Wenbo Zhi,&nbsp;Mary Gbadebo,&nbsp;Frederick Bonsack,&nbsp;Hongyan Xu,&nbsp;Sangeetha Sukumari-Ramesh","doi":"10.1016/j.nbd.2025.106936","DOIUrl":"10.1016/j.nbd.2025.106936","url":null,"abstract":"<div><div>Aging is an independent predictor of adverse outcomes after intracerebral hemorrhage (ICH), a stroke subtype with no effective treatment. Despite the expected increase in the incidence of ICH due to population aging and the widespread use of anticoagulants, preclinical studies with aged animal subjects are lacking, and the pathophysiology of ICH in aged subjects has yet to be defined. Herein, we attempt to characterize the brain proteomic changes after ICH using an unbiased label- free quantitative proteomics approach and bioinformatics. To this end, aged male and female mice (18–24 months old) were subjected to sham/ICH. Mice were euthanized on day 3 post-surgery, and ipsilateral brain tissue was collected and subjected to LC-MS/MS analysis. Considering sex as a biological variable, the data derived from males and females were separately analyzed. The proteomics analysis revealed 133 differentially expressed proteins (DEPs) between the sham and ICH groups in male subjects. Among the DEPs, 98 proteins were downregulated, and 35 proteins were upregulated after ICH, compared to sham. In aged female mice, 315 DEPs were identified, of which 221 proteins were downregulated, and 94 proteins were upregulated after ICH compared to sham. The mass spectrometry data was validated using immunohistochemistry or western blot analysis, and the bioinformatics analysis revealed a comprehensive understanding of the signaling pathways associated with ICH. Some DEPs in both aged male and female mice that could play roles in ICH pathology were 14–3-3 proteins and S100-A9. The study also revealed that mitochondrial dysfunction could be a critical regulator of ICH-induced acute brain damage. Overall, the generated proteomics data could help develop hypothesis-driven functional analysis and delineate the complex pathobiology of ICH.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106936"},"PeriodicalIF":5.1,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991090","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}
引用次数: 0
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