Acta Neuropathologica Communications最新文献

{"title":"Crucial role of Aquaporin-4 extended isoform in brain water Homeostasis and Amyloid-β clearance: implications for Edema and neurodegenerative diseases.","authors":"Pasqua Abbrescia, Gianluca Signorile, Onofrio Valente, Claudia Palazzo, Antonio Cibelli, Grazia Paola Nicchia, Antonio Frigeri","doi":"10.1186/s40478-024-01870-4","DOIUrl":"10.1186/s40478-024-01870-4","url":null,"abstract":"<p><p>The water channel aquaporin-4 (AQP4) is crucial for water balance in the mammalian brain. AQP4 has two main canonical isoforms, M23, which forms supramolecular structures called Orthogonal Arrays of Particles (OAP) and M1, which does not, along with two extended isoforms (M23ex and M1ex). This study examines these isoforms' roles, particularly AQP4ex, which influences water channel activity and localization at the blood-brain barrier. Using mice lacking both AQP4ex isoforms (AQP4ex-KO) and lacking both AQP4M23 isoforms (OAP-null) mice, we explored brain water dynamics under osmotic stress induced by an acute water intoxication (AWI) model. AQP4ex-KO mice had lower basal brain water content than WT and OAP-null mice. During AWI, brain water content increased rapidly in WT and AQP4ex-KO mice, but was delayed in OAP-null mice. AQP4ex-KO mice had the highest water content increase at 20 min. Immunoblot analysis showed stable total AQP4 in WT mice initially, with increases at 30 min. AQP4ex and its phosphorylated form (p-AQP4ex) levels rose quickly, but the p-AQP4ex/AQP4ex ratio dropped at 20 min. AQP4ex-KO mice showed a compensatory rise in canonical AQP4 at 20 min post-AWI. These findings highlight the important role of AQP4ex in water content dynamics in both normal and pathological states. To evaluate brain waste clearance, amyloid-β (Aβ) removal was assessed using a fluorescent Aβ intra-parenchyma injection model. AQP4ex-KO mice demonstrated markedly impaired Aβ clearance, with extended diffusion distances and reduced fluorescence in cervical lymph nodes, indicating inefficient drainage from the brain parenchyma. Mechanistically, the polarization of AQP4 at astrocytic endfeet is essential for efficient clearance flow, aiding interstitial fluid movement into the CSF and lymphatic system. In AQP4ex-KO mice, disrupted polarization forces reliance on slower, passive diffusion for solute clearance, significantly reducing Aβ removal efficiency and altering extracellular space dynamics. Our results underscore the importance of AQP4ex in both brain water homeostasis and solute clearance, particularly Aβ. These findings highlight AQP4ex as a potential therapeutic target for enhancing waste clearance mechanisms in the brain, which could have significant implications for treating brain edema and neurodegenerative diseases like Alzheimer's.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"159"},"PeriodicalIF":6.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387204","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":"Non-supratentorial YAP1- fused ependymomas: report of two cases.","authors":"Leiming Wang, Lei Cheng, Yongjuan Fu, Hua Dong, Yanlei Xiong, Dehong Lu, Yueshan Piao, Lianghong Teng","doi":"10.1186/s40478-024-01862-4","DOIUrl":"10.1186/s40478-024-01862-4","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"158"},"PeriodicalIF":6.2,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378963","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":"Hyperspectral retinal imaging in Alzheimer's disease and age-related macular degeneration: a review.","authors":"Xiaoxi Du, Jongchan Park, Ruixuan Zhao, R Theodore Smith, Yosef Koronyo, Maya Koronyo-Hamaoui, Liang Gao","doi":"10.1186/s40478-024-01868-y","DOIUrl":"10.1186/s40478-024-01868-y","url":null,"abstract":"<p><p>While Alzheimer's disease and other neurodegenerative diseases have traditionally been viewed as brain disorders, there is growing evidence indicating their manifestation in the eyes as well. The retina, being a developmental extension of the brain, represents the only part of the central nervous system that can be noninvasively imaged at a high spatial resolution. The discovery of the specific pathological hallmarks of Alzheimer's disease in the retina of patients holds great promise for disease diagnosis and monitoring, particularly in the early stages where disease progression can potentially be slowed. Among various retinal imaging methods, hyperspectral imaging has garnered significant attention in this field. It offers a label-free approach to detect disease biomarkers, making it especially valuable for large-scale population screening efforts. In this review, we discuss recent advances in the field and outline the current bottlenecks and enabling technologies that could propel this field toward clinical translation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"157"},"PeriodicalIF":6.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370696","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":"Targeting the TDP-43 low complexity domain blocks spreading of pathology in a mouse model of ALS/FTD.","authors":"Elodie Chevalier, Mickael Audrain, Monisha Ratnam, Romain Ollier, Aline Fuchs, Kasia Piorkowska, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina, Tariq Afroz","doi":"10.1186/s40478-024-01867-z","DOIUrl":"10.1186/s40478-024-01867-z","url":null,"abstract":"<p><p>Abnormal cytoplasmic localization and accumulation of pathological transactive response DNA binding protein of 43 kDa (TDP-43) underlies several devastating diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). A key element is the correlation between disease progression and spatio-temporal propagation of TDP-43-mediated pathology in the central nervous system. Several lines of evidence support the concept of templated aggregation and cell to cell spreading of pathological TDP-43. To further investigate this mechanism in vivo, we explored the efficacy of capturing and masking the seeding-competent region of extracellular TDP-43 species. For this, we generated a novel monoclonal antibody (mAb), ACI-6677, that targets the pathogenic protease-resistant amyloid core of TDP-43. ACI-6677 has a picomolar binding affinity for TDP-43 and is capable of binding to all C-terminal TDP-43 fragments. In vitro, ACI-6677 inhibited TDP-43 aggregation and boosted removal of pathological TDP-43 aggregates by phagocytosis. When injecting FTLD-TDP brain extracts unilaterally in the CamKIIa-hTDP-43NLSm mouse model, ACI-6677 significantly limited the induction of phosphorylated TDP-43 (pTDP-43) inclusions. Strikingly, on the contralateral side, the mAb significantly prevented pTDP-43 inclusion appearance exemplifying blocking of the spreading process. Taken together, these data demonstrate for the first time that an immunotherapy targeting the protease-resistant amyloid core of TDP-43 has the potential to restrict spreading, substantially slowing or stopping progression of disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"156"},"PeriodicalIF":6.2,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11448013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370697","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":"Correction: Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort.","authors":"Nobuhide Hayashi, Junya Fukai, Hirokazu Nakatogawa, Hiroshi Kawaji, Ema Yoshioka, Yoshinori Kodama, Kosuke Nakajo, Takehiro Uda, Kentaro Naito, Noriyuki Kijima, Yoshiko Okita, Naoki Kagawa, Yoshinobu Takahashi, Naoya Hashimoto, Hideyuki Arita, Koji Takano, Daisuke Sakamoto, Tomoko Iida, Yoshiki Arakawa, Takeshi Kawauchi, Yukihiko Sonoda, Yuta Mitobe, Kenichi Ishibashi, Masahide Matsuda, Takamune Achiha, Takahiro Tomita, Masahiro Nonaka, Keijiro Hara, Noriyoshi Takebe, Takashi Tsuzuki, Yoshikazu Nakajima, Shiro Ohue, Nobuyuki Nakajima, Akira Watanabe, Akihiro Inoue, Masao Umegaki, Daisuke Kanematsu, Asako Katsuma, Miho Sumida, Tomoko Shofuda, Masayuki Mano, Manabu Kinoshita, Kanji Mori, Naoyuki Nakao, Yonehiro Kanemura","doi":"10.1186/s40478-024-01863-3","DOIUrl":"10.1186/s40478-024-01863-3","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"155"},"PeriodicalIF":6.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360912","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":"Trem2-deficiency aggravates and accelerates age-related myelin degeneration","authors":"Tyler J. McCray, Logan M. Bedford, Stephanie J. Bissel, Bruce T. Lamb","doi":"10.1186/s40478-024-01855-3","DOIUrl":"https://doi.org/10.1186/s40478-024-01855-3","url":null,"abstract":"Aging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"77 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142269876","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":"Correction: Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19","authors":"Nathalie A. Lengacher, Julianna J. Tomlinson, Ann‑Kristin Jochum, Jonas Franz, Omar Hasan Ali, Lukas Flatz, Wolfram Jochum, Josef Penninger, Christine Stadelmann, John M. Woulfe, Michael G. Schlossmacher","doi":"10.1186/s40478-024-01843-7","DOIUrl":"https://doi.org/10.1186/s40478-024-01843-7","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Correction: Acta Neuropathologica Communications (2024) 12:70&lt;/b&gt; &lt;b&gt;https://doi.org/10.1186/s40478-024-01761-8&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Following publication of the original article [1], in Fig. 3, B panel image “1” is incorrect. The incorrect section of the Fig. 3B and corrected version of full Fig. 3 is given below.&lt;/p&gt;&lt;p&gt;Incorrect Fig. 3, Panel B, Image 1:&lt;/p&gt;&lt;figure&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Figa_HTML.jpg?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure a\" aria-describedby=\"Figa\" height=\"813\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Figa_HTML.jpg\" width=\"685\"/&gt;&lt;/picture&gt;&lt;/figure&gt;&lt;p&gt;Figure 3 and caption.&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 3&lt;/b&gt;&lt;/figcaption&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Fig3_HTML.png?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure 3\" aria-describedby=\"Fig3\" height=\"842\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40478-024-01843-7/MediaObjects/40478_2024_1843_Fig3_HTML.png\" width=\"685\"/&gt;&lt;/picture&gt;&lt;p&gt;Anti-phosphorylated α-synuclein reactivity in the anterior olfactory nucleus. &lt;b&gt;A&lt;/b&gt; Example of immunohistochemical staining for p-αSyn in the human olfactory bulb, highlighting the AON from a person with Parkinson disease and related dementia [case #39]. Scale bars represent 100 μM. &lt;b&gt;B&lt;/b&gt; Representative images of semi-quantitative scoring of pathology, ranging from 0 to 5, in the AON. Scale bars represent 50 μM. &lt;b&gt;C&lt;/b&gt; Percentage of cases in each group that have a pathology score of 1 or higher. &lt;b&gt;D&lt;/b&gt; Correlation between age and p-αSyn pathology scores in the control group (HCO and NCO combined) and COVID19 + cases. &lt;b&gt;E&lt;/b&gt; Distribution of pathology scores for each group. Filled blue squares in &lt;b&gt;D&lt;/b&gt; and &lt;b&gt;E&lt;/b&gt; indicate COVID19 + cases suspected of having incidental LBD at autopsy; filled dark yellow diamond in &lt;b&gt;E&lt;/b&gt; indicates AD case diagnosed with mixed pathology at autopsy, and filled green triangle indicates MSA case. Significance was determined using Kruskal–Wallis test with Dunn’s post-hoc (&lt;b&gt;E&lt;/b&gt;), where **** indicates &lt;i&gt;p&lt;/i&gt; ≤ 0.0001. Abbreviations for disease groups as in Fig. 1&lt;/p&gt;&lt;span&gt;Full size image&lt;/span&gt;&lt;svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"&gt;&lt;use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"&gt;&lt;/use&gt;&lt;/svg&gt;&lt;/figure&gt;&lt;p&gt;The original article has been corrected.&lt;/p&gt;&lt;ol data-track-component=\"outbound reference\" data-track-context=\"references section\"&gt;&lt;li data-counter=\"1.\"&gt;&lt;p&gt;Lengacher NA, Tomlinson JJ, Jochum AK et al (2024) Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19. Acta Neuropathol Commun 12:","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"20 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263151","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":"Molecular pathology, developmental changes and synaptic dysfunction in (pre-) symptomatic human C9ORF72-ALS/FTD cerebral organoids","authors":"Astrid T. van der Geest, Channa E. Jakobs, Tijana Ljubikj, Christiaan F. M. Huffels, Marta Cañizares Luna, Renata Vieira de Sá, Youri Adolfs, Marina de Wit, Daan H. Rutten, Marthe Kaal, Maria M. Zwartkruis, Mireia Carcolé, Ewout J. N. Groen, Elly M. Hol, Onur Basak, Adrian M. Isaacs, Henk-Jan Westeneng, Leonard H. van den Berg, Jan H. Veldink, Domino K. Schlegel, R. Jeroen Pasterkamp","doi":"10.1186/s40478-024-01857-1","DOIUrl":"https://doi.org/10.1186/s40478-024-01857-1","url":null,"abstract":"A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"24 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263152","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":"Real-world experience with circulating tumor DNA in cerebrospinal fluid from patients with central nervous system tumors","authors":"Richard A. Hickman, Alexandra M. Miller, Bridget M. Holle, Justin Jee, Si-Yang Liu, Dara Ross, Helena Yu, Gregory J. Riely, Christina Ombres, Alexandra N. Gewirtz, Anne S. Reiner, Subhiksha Nandakumar, Adam Price, Thomas J. Kaley, Maya S. Graham, Chad Vanderbilt, Satshil Rana, Katherine Hill, Kiana Chabot, Carl Campos, Khedoudja Nafa, Neerav Shukla, Matthias Karajannis, Bob Li, Michael Berger, Marc Ladanyi, Elena Pentsova, Adrienne Boire, A. Rose Brannon, Tejus Bale, Ingo K. Mellinghoff, Maria E. Arcila","doi":"10.1186/s40478-024-01846-4","DOIUrl":"https://doi.org/10.1186/s40478-024-01846-4","url":null,"abstract":"The characterization of genetic alterations in tumor samples has become standard practice for many human cancers to achieve more precise disease classification and guide the selection of targeted therapies. Cerebrospinal fluid (CSF) can serve as a source of tumor DNA in patients with central nervous system (CNS) cancer. We performed comprehensive profiling of CSF circulating tumor DNA (ctDNA) in 711 patients using an FDA-authorized platform (MSK-IMPACT™) in a hospital laboratory. We identified genetic alterations in 489/922 (53.0%) CSF samples with clinically documented CNS tumors. None of 85 CSF samples from patients without CNS tumors had detectable ctDNA. The distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Repeated CSF ctDNA examinations from the same patients identified clonal evolution and emergence of resistance mechanisms. ctDNA detection was associated with shortened overall survival following CSF collection. Next-generation sequencing of CSF, collected through a minimally invasive lumbar puncture in a routine hospital setting, provides clinically actionable cancer genotype information in a large fraction of patients with CNS tumors.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"16 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263153","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":"Evaluation of Rho kinase inhibitor effects on neuroprotection and neuroinflammation in an ex-vivo retinal explant model","authors":"Élodie Reboussin, Paul Bastelica, Ilyes Benmessabih, Arnaud Cordovilla, Cécile Delarasse, Annabelle Réaux-Le Goazigo, Françoise Brignole-Baudouin, Céline Olmière, Christophe Baudouin, Juliette Buffault, Stéphane Mélik Parsadaniantz","doi":"10.1186/s40478-024-01859-z","DOIUrl":"https://doi.org/10.1186/s40478-024-01859-z","url":null,"abstract":"Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"30 1","pages":""},"PeriodicalIF":7.1,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263150","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}