Pub Date : 2025-01-10DOI: 10.1016/j.nbd.2025.106802
Hamza Arshad , Shehab Eid , Surabhi Mehra , Declan Williams , Lech Kaczmarczyk , Erica Stuart , Walker S. Jackson , Gerold Schmitt-Ulms , Joel C. Watts
Bank voles are susceptible to prion strains from many different species, yet the molecular mechanisms underlying the ability of bank vole prion protein (BVPrP) to function as a universal prion acceptor remain unclear. Potential differences in molecular environments and protein interaction networks on the cell surface of brain cells may contribute to BVPrP's unusual behavior. To test this hypothesis, we generated knock-in mice that express physiological levels of BVPrP (M109 isoform) and employed mass spectrometry to compare the interactomes of mouse (Mo) PrP and BVPrP following mild in vivo crosslinking of brain tissue. Substantial overlap was observed between the top interactors for BVPrP and MoPrP, with established PrP-interactors such as neural cell adhesion molecules, subunits of Na+/K+-ATPases, and contactin-1 being equally present in the two interactomes. We conclude that the molecular environments of BVPrP and MoPrP in the brains of mice are very similar. This suggests that the unorthodox properties of BVPrP are unlikely to be mediated by differential interactions with other proteins.
{"title":"The brain interactome of a permissive prion replication substrate","authors":"Hamza Arshad , Shehab Eid , Surabhi Mehra , Declan Williams , Lech Kaczmarczyk , Erica Stuart , Walker S. Jackson , Gerold Schmitt-Ulms , Joel C. Watts","doi":"10.1016/j.nbd.2025.106802","DOIUrl":"10.1016/j.nbd.2025.106802","url":null,"abstract":"<div><div>Bank voles are susceptible to prion strains from many different species, yet the molecular mechanisms underlying the ability of bank vole prion protein (BVPrP) to function as a universal prion acceptor remain unclear. Potential differences in molecular environments and protein interaction networks on the cell surface of brain cells may contribute to BVPrP's unusual behavior. To test this hypothesis, we generated knock-in mice that express physiological levels of BVPrP (M109 isoform) and employed mass spectrometry to compare the interactomes of mouse (Mo) PrP and BVPrP following mild in vivo crosslinking of brain tissue. Substantial overlap was observed between the top interactors for BVPrP and MoPrP, with established PrP-interactors such as neural cell adhesion molecules, subunits of Na<sup>+</sup>/K<sup>+</sup>-ATPases, and contactin-1 being equally present in the two interactomes. We conclude that the molecular environments of BVPrP and MoPrP in the brains of mice are very similar. This suggests that the unorthodox properties of BVPrP are unlikely to be mediated by differential interactions with other proteins.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106802"},"PeriodicalIF":5.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971683","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}
Pub Date : 2025-01-07DOI: 10.1016/j.nbd.2025.106795
Angela K. Nietz , Laurentiu S. Popa , Russell E. Carter , Morgan L. Gerhart , Keerthi Manikonda , Laura P.W. Ranum , Timothy J. Ebner
Spinocerebellar Ataxia Type 8 (SCA8) is an inherited neurodegenerative disease caused by a bidirectionally expressed CTG•CAG expansion mutation in the ATXN8 and ATXN8OS genes. While SCA8 patients have motor abnormalities, patients may also exhibit psychiatric symptoms and cognitive dysfunction. It is difficult to elucidate how the disease alters brain function in areas with little or no degeneration producing both motor and cognitive symptoms. Using transparent polymer skulls and CNS-wide GCaMP6f expression, we studied neocortical networks throughout SCA8 progression using wide-field Ca2+ imaging in a transgenic mouse model of SCA8. Compared to wild-type controls, neocortical networks in SCA8+ mice were hyperconnected globally, which leads to network configurations with increased global efficiency and centrality. At the regional level, significant network changes occurred in nearly all cortical regions, however mainly involved sensory and association cortices. Changes in functional connectivity in anterior motor regions worsened later in the disease. Near perfect decoding of animal genotype was obtained using a generalized linear model based on canonical correlation strengths between activity in cortical regions. The major contributors to decoding were concentrated in the somatosensory, higher visual and retrosplenial cortices and occasionally extended into the motor regions, demonstrating that the areas with the largest network changes are predictive of disease state.
{"title":"Cerebral cortical functional hyperconnectivity in a mouse model of spinocerebellar ataxia type 8 (SCA8)","authors":"Angela K. Nietz , Laurentiu S. Popa , Russell E. Carter , Morgan L. Gerhart , Keerthi Manikonda , Laura P.W. Ranum , Timothy J. Ebner","doi":"10.1016/j.nbd.2025.106795","DOIUrl":"10.1016/j.nbd.2025.106795","url":null,"abstract":"<div><div>Spinocerebellar Ataxia Type 8 (SCA8) is an inherited neurodegenerative disease caused by a bidirectionally expressed CTG•CAG expansion mutation in the <em>ATXN8</em> and <em>ATXN8OS</em> genes. While SCA8 patients have motor abnormalities, patients may also exhibit psychiatric symptoms and cognitive dysfunction. It is difficult to elucidate how the disease alters brain function in areas with little or no degeneration producing both motor and cognitive symptoms. Using transparent polymer skulls and CNS-wide GCaMP6f expression, we studied neocortical networks throughout SCA8 progression using wide-field Ca<sup>2+</sup> imaging in a transgenic mouse model of SCA8. Compared to wild-type controls, neocortical networks in SCA8+ mice were hyperconnected globally, which leads to network configurations with increased global efficiency and centrality. At the regional level, significant network changes occurred in nearly all cortical regions, however mainly involved sensory and association cortices. Changes in functional connectivity in anterior motor regions worsened later in the disease. Near perfect decoding of animal genotype was obtained using a generalized linear model based on canonical correlation strengths between activity in cortical regions. The major contributors to decoding were concentrated in the somatosensory, higher visual and retrosplenial cortices and occasionally extended into the motor regions, demonstrating that the areas with the largest network changes are predictive of disease state.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106795"},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951875","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106760
Hongling Zhu , Y. Terry Lee , Colleen Byrnes , Jabili Angina , Danielle A. Springer , Galina Tuymetova , Mari Kono , Cynthia J. Tifft , Richard L. Proia
Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the HEXB gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function. In this study, Sandhoff disease model mice exhibited reduced mTOR signaling in the brain. To test if restoring mTOR signaling could improve the disease phenotype, we genetically reduced expression of the mTOR inhibitor Tsc2 in these mice. Sandhoff disease mice with reactivated mTOR signaling displayed increased survival rates and motor function, especially in females, increased dendritic-spine density, and reduced neurodegeneration. Tsc2 reduction also partially rescued aberrant synaptic function–related gene expression. These findings imply that enhancing mTOR signaling could be a potential therapeutic strategy for lysosomal-based neurodegenerative diseases.
{"title":"Reactivation of mTOR signaling slows neurodegeneration in a lysosomal sphingolipid storage disease","authors":"Hongling Zhu , Y. Terry Lee , Colleen Byrnes , Jabili Angina , Danielle A. Springer , Galina Tuymetova , Mari Kono , Cynthia J. Tifft , Richard L. Proia","doi":"10.1016/j.nbd.2024.106760","DOIUrl":"10.1016/j.nbd.2024.106760","url":null,"abstract":"<div><div>Sandhoff disease, a lysosomal storage disorder, is caused by pathogenic variants in the <em>HEXB</em> gene, resulting in the loss of β-hexosaminidase activity and accumulation of sphingolipids including GM2 ganglioside. This accumulation occurs primarily in neurons, and leads to progressive neurodegeneration through a largely unknown process. Lysosomal storage diseases often exhibit dysfunctional mTOR signaling, a pathway crucial for proper neuronal development and function. In this study, Sandhoff disease model mice exhibited reduced mTOR signaling in the brain. To test if restoring mTOR signaling could improve the disease phenotype, we genetically reduced expression of the mTOR inhibitor Tsc2 in these mice. Sandhoff disease mice with reactivated mTOR signaling displayed increased survival rates and motor function, especially in females, increased dendritic-spine density, and reduced neurodegeneration. Tsc2 reduction also partially rescued aberrant synaptic function–related gene expression. These findings imply that enhancing mTOR signaling could be a potential therapeutic strategy for lysosomal-based neurodegenerative diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106760"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794865","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106762
Santtu Hellström , Antti Sajanti , Abhinav Srinath , Carolyn Bennett , Romuald Girard , Aditya Jhaveri , Ying Cao , Johannes Falter , Janek Frantzén , Fredrika Koskimäki , Seán B. Lyne , Tomi Rantamäki , Riikka Takala , Jussi P. Posti , Susanna Roine , Sulo Kolehmainen , Kenneth Nazir , Miro Jänkälä , Jukka Puolitaival , Melissa Rahi , Janne Koskimäki
Lipidomic alterations have been associated with various neurological diseases. Examining temporal changes in serum lipidomic profiles, irrespective of injury type, reveals promising prognostic indicators. In this longitudinal prospective observational study, serum samples were collected early (46 ± 24 h) and late (142 ± 52 h) post-injury from 70 patients with ischemic stroke, aneurysmal subarachnoid hemorrhage, and traumatic brain injury that had outcomes dichotomized as favorable (modified Rankin Scores (mRS) 0–3) and unfavorable (mRS 4–6) three months post-injury. Lipidomic profiling of 1153 lipids, analyzed using statistical and machine learning methods, identified 153 lipids with late-stage significant outcome differences. Supervised machine learning pinpointed 12 key lipids, forming a combinatory prognostic equation with high discriminatory power (AUC 94.7 %, sensitivity 89 %, specificity 92 %; p < 0.0001). Enriched functions of the identified lipids were related to sphingolipid signaling, glycerophospholipid metabolism, and necroptosis (p < 0.05, FDR-corrected). The study underscores the dynamic nature of lipidomic profiles in acute brain injuries, emphasizing late-stage distinctions and proposing lipids as significant prognostic markers, transcending injury types. These findings advocate further exploration of lipidomic changes for a comprehensive understanding of pathobiological roles and enhanced prediction for recovery trajectories.
{"title":"Common lipidomic signatures across distinct acute brain injuries in patient outcome prediction","authors":"Santtu Hellström , Antti Sajanti , Abhinav Srinath , Carolyn Bennett , Romuald Girard , Aditya Jhaveri , Ying Cao , Johannes Falter , Janek Frantzén , Fredrika Koskimäki , Seán B. Lyne , Tomi Rantamäki , Riikka Takala , Jussi P. Posti , Susanna Roine , Sulo Kolehmainen , Kenneth Nazir , Miro Jänkälä , Jukka Puolitaival , Melissa Rahi , Janne Koskimäki","doi":"10.1016/j.nbd.2024.106762","DOIUrl":"10.1016/j.nbd.2024.106762","url":null,"abstract":"<div><div>Lipidomic alterations have been associated with various neurological diseases. Examining temporal changes in serum lipidomic profiles, irrespective of injury type, reveals promising prognostic indicators. In this longitudinal prospective observational study, serum samples were collected early (46 ± 24 h) and late (142 ± 52 h) post-injury from 70 patients with ischemic stroke, aneurysmal subarachnoid hemorrhage, and traumatic brain injury that had outcomes dichotomized as favorable (modified Rankin Scores (mRS) 0–3) and unfavorable (mRS 4–6) three months post-injury. Lipidomic profiling of 1153 lipids, analyzed using statistical and machine learning methods, identified 153 lipids with late-stage significant outcome differences. Supervised machine learning pinpointed 12 key lipids, forming a combinatory prognostic equation with high discriminatory power (AUC 94.7 %, sensitivity 89 %, specificity 92 %; <em>p</em> < 0.0001). Enriched functions of the identified lipids were related to sphingolipid signaling, glycerophospholipid metabolism, and necroptosis (<em>p</em> < 0.05, FDR-corrected). The study underscores the dynamic nature of lipidomic profiles in acute brain injuries, emphasizing late-stage distinctions and proposing lipids as significant prognostic markers, transcending injury types. These findings advocate further exploration of lipidomic changes for a comprehensive understanding of pathobiological roles and enhanced prediction for recovery trajectories.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106762"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813699","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106769
Bilal Moiz , Matthew Walls , Viviana Alpizar Vargas , Anirudh Addepalli , Callie Weber , Andrew Li , Ganesh Sriram , Alisa Morss Clyne
Niemann Pick Disease Type C (NP-C), a rare neurogenetic disease with no known cure, is caused by mutations in the cholesterol trafficking protein NPC1. Brain microvascular endothelial cells (BMEC) are thought to play a critical role in the pathogenesis of several neurodegenerative diseases; however, little is known about how these cells are altered in NP-C. In this study, we investigated how NPC1 inhibition perturbs BMEC metabolism in human induced pluripotent stem cell-derived BMEC (hiBMEC). We incorporated extracellular metabolite and isotope labeling data into an instationary metabolic flux analysis (INST-MFA) model to estimate intracellular metabolic fluxes. We found that NPC1 inhibition significantly increased glycolysis and pentose phosphate pathway flux while decreasing mitochondrial metabolism. These changes may have been driven by gene expression changes due to increased cholesterol biosynthesis, in addition to mitochondrial cholesterol accumulation. We corroborated these findings in primary BMEC, an alternative in vitro human brain endothelial model. Finally, we found that co-treatment with hydroxypropyl-β cyclodextrin (HPβCD) partially restored metabolic phenotype in U18666A-treated BMECs, suggesting that this drug may have therapeutic effects on the brain endothelium in NP-C. Together, our data highlight the importance of NPC1 in BMEC metabolism and implicate brain endothelial dysfunction in NP-C pathogenesis.
{"title":"Instationary metabolic flux analysis reveals that NPC1 inhibition increases glycolysis and decreases mitochondrial metabolism in brain microvascular endothelial cells","authors":"Bilal Moiz , Matthew Walls , Viviana Alpizar Vargas , Anirudh Addepalli , Callie Weber , Andrew Li , Ganesh Sriram , Alisa Morss Clyne","doi":"10.1016/j.nbd.2024.106769","DOIUrl":"10.1016/j.nbd.2024.106769","url":null,"abstract":"<div><div>Niemann Pick Disease Type C (NP-C), a rare neurogenetic disease with no known cure, is caused by mutations in the cholesterol trafficking protein NPC1. Brain microvascular endothelial cells (BMEC) are thought to play a critical role in the pathogenesis of several neurodegenerative diseases; however, little is known about how these cells are altered in NP-C. In this study, we investigated how NPC1 inhibition perturbs BMEC metabolism in human induced pluripotent stem cell-derived BMEC (hiBMEC). We incorporated extracellular metabolite and isotope labeling data into an instationary metabolic flux analysis (INST-MFA) model to estimate intracellular metabolic fluxes. We found that NPC1 inhibition significantly increased glycolysis and pentose phosphate pathway flux while decreasing mitochondrial metabolism. These changes may have been driven by gene expression changes due to increased cholesterol biosynthesis, in addition to mitochondrial cholesterol accumulation. We corroborated these findings in primary BMEC, an alternative in vitro human brain endothelial model. Finally, we found that co-treatment with hydroxypropyl-β cyclodextrin (HPβCD) partially restored metabolic phenotype in U18666A-treated BMECs, suggesting that this drug may have therapeutic effects on the brain endothelium in NP-C. Together, our data highlight the importance of NPC1 in BMEC metabolism and implicate brain endothelial dysfunction in NP-C pathogenesis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106769"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872697","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106757
Nolwazi Z. Gcwensa , Dreson L. Russell , Khaliah Y. Long , Charlotte F. Brzozowski , Xinran Liu , Karen L. Gamble , Rita M. Cowell , Laura A. Volpicelli-Daley
{"title":"Corrigendum to “Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala” [Neurobiology of Disease 199 (2024) 106595]","authors":"Nolwazi Z. Gcwensa , Dreson L. Russell , Khaliah Y. Long , Charlotte F. Brzozowski , Xinran Liu , Karen L. Gamble , Rita M. Cowell , Laura A. Volpicelli-Daley","doi":"10.1016/j.nbd.2024.106757","DOIUrl":"10.1016/j.nbd.2024.106757","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106757"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951633","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106768
Jianbin Sun , Na Sai , Tong Zhang , Chaoying Tang , Shuhang Fan , Qin Wang , Da Liu , Xianhai Zeng , Juanjuan Li , Weiwei Guo , Shiming Yang , Weiju Han
Repeated low-intensity noise exposure is prevalent in industrialized societies. It has long been considered risk-free until recent evidence suggests that the temporary threshold shift (TTS) induced by such exposure might be a high-risk factor for hearing loss. This study was conducted to further investigate the manner in which repeated low-intensity noise exposure contributed to hearing damage. Two-month-old C57BL/6 J mice were exposed to white noise at 96 dB SPL for 8 h per day over 7 days to induce TTS. Auditory brainstem response (ABR) was monitored to assess changes in hearing thresholds, tracking the effects of noise exposure until the mice reached 12 months of age. Our results indicated that noise-exposed mice exhibited accelerated age-related hearing loss spanning from high to low frequencies. Proteomics analysis revealed an upregulation in the receptor for the advanced glycation end-products (RAGE) signaling pathway, which was associated with an activated inflammatory response, vascular injury, and mitochondrial and synaptic dysfunction. Further analysis confirmed increased levels of inflammatory cytokines in the cochlear lymph fluid and significant macrophages infiltration in the cochlear lateral wall, accompanied by hyperpermeability of the blood-labyrinth barrier. Additionally, degenerated mitochondria in the outer hair cells and decreased synaptic ribbons in the inner hair cells were also observed. These pathological changes indicated that noise exposure damages the cochlear cellular components, increasing the cochlear susceptibility to age-related stress. Our findings suggest that TTS caused by repeated low-intensity noise exposure correlates with a severe sensorineural hearing loss during aging; targeting the RAGE signaling pathway may be a promising strategy to mitigate damage from low-intensity noise and slow down the progression of age-related hearing loss.
重复的低强度噪音暴露在工业化社会中很普遍。长期以来，它一直被认为是无风险的，直到最近的证据表明，由这种暴露引起的暂时阈值转移（TTS）可能是听力损失的高风险因素。本研究的目的是进一步研究反复接触低强度噪音对听力损害的影响。将2月龄C57BL/6 J小鼠暴露于96 dB SPL的白噪声中，每天8 h，连续7 天诱导TTS。监测听觉脑干反应（ABR）以评估听力阈值的变化，跟踪噪声暴露的影响，直到小鼠达到12 个月大。我们的研究结果表明，噪声暴露的小鼠表现出加速年龄相关的听力损失，从高频到低频。蛋白质组学分析显示，晚期糖基化终产物（RAGE）信号通路受体上调，这与激活的炎症反应、血管损伤、线粒体和突触功能障碍有关。进一步分析证实，耳蜗淋巴液中炎性细胞因子水平升高，耳蜗侧壁有明显的巨噬细胞浸润，并伴有血迷宫屏障的高渗透性。外毛细胞线粒体退化，内毛细胞突触带减少。这些病理变化表明，噪声暴露损害了耳蜗细胞成分，增加了耳蜗对年龄相关应激的易感性。我们的研究结果表明，反复低强度噪声暴露引起的TTS与衰老过程中严重的感音神经性听力损失有关；靶向RAGE信号通路可能是一种有希望的策略，可以减轻低强度噪音造成的损伤，并减缓与年龄相关的听力损失的进展。
{"title":"Repeated low-intensity noise exposure exacerbates age-related hearing loss via RAGE signaling pathway","authors":"Jianbin Sun , Na Sai , Tong Zhang , Chaoying Tang , Shuhang Fan , Qin Wang , Da Liu , Xianhai Zeng , Juanjuan Li , Weiwei Guo , Shiming Yang , Weiju Han","doi":"10.1016/j.nbd.2024.106768","DOIUrl":"10.1016/j.nbd.2024.106768","url":null,"abstract":"<div><div>Repeated low-intensity noise exposure is prevalent in industrialized societies. It has long been considered risk-free until recent evidence suggests that the temporary threshold shift (TTS) induced by such exposure might be a high-risk factor for hearing loss. This study was conducted to further investigate the manner in which repeated low-intensity noise exposure contributed to hearing damage. Two-month-old C57BL/6 J mice were exposed to white noise at 96 dB SPL for 8 h per day over 7 days to induce TTS. Auditory brainstem response (ABR) was monitored to assess changes in hearing thresholds, tracking the effects of noise exposure until the mice reached 12 months of age. Our results indicated that noise-exposed mice exhibited accelerated age-related hearing loss spanning from high to low frequencies. Proteomics analysis revealed an upregulation in the receptor for the advanced glycation end-products (RAGE) signaling pathway, which was associated with an activated inflammatory response, vascular injury, and mitochondrial and synaptic dysfunction. Further analysis confirmed increased levels of inflammatory cytokines in the cochlear lymph fluid and significant macrophages infiltration in the cochlear lateral wall, accompanied by hyperpermeability of the blood-labyrinth barrier. Additionally, degenerated mitochondria in the outer hair cells and decreased synaptic ribbons in the inner hair cells were also observed. These pathological changes indicated that noise exposure damages the cochlear cellular components, increasing the cochlear susceptibility to age-related stress. Our findings suggest that TTS caused by repeated low-intensity noise exposure correlates with a severe sensorineural hearing loss during aging; targeting the RAGE signaling pathway may be a promising strategy to mitigate damage from low-intensity noise and slow down the progression of age-related hearing loss.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106768"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854695","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106758
Jiaotao Xing , Ying Li , Jiali Hu , Liyao Gu , Guanghua Sun , Xiangle Li
Irritable bowel syndrome (IBS) is a functional bowel disorder defined by recurrent abdominal pain, coupled with irregular bowel habits and alterations in the frequency as well as the consistency of stool. At present, IBS is considered as a disease of gut-brain interaction, and an increasing number of studies are focusing on the brain-gut axis. However, the brain regions associated with IBS have not been fully studied yet. In this study, we utilized the chronic restraint stress (CRS) model to evoke IBS-like symptoms in mice, which were accompanied by anxiety-like behaviors and hyperalgesia. Through cFOS staining, we observed the activation of the lateral periaqueductal gray (LPAG) in the mice after CRS. By inhibiting the activity of the LPAG through tetanus toxin or chemogenetics, we found that IBS-like symptoms could be relieved, whereas chemogenetic activation of the LPAG induced IBS-like symptoms. Finally, we utilized the classic analgesic drug sufentanil and found that it could alleviate CRS-induced IBS-like symptoms.
{"title":"Lateral periaqueductal gray participate in the regulation of irritable bowel syndrome induced by chronic restraint stress","authors":"Jiaotao Xing , Ying Li , Jiali Hu , Liyao Gu , Guanghua Sun , Xiangle Li","doi":"10.1016/j.nbd.2024.106758","DOIUrl":"10.1016/j.nbd.2024.106758","url":null,"abstract":"<div><div>Irritable bowel syndrome (IBS) is a functional bowel disorder defined by recurrent abdominal pain, coupled with irregular bowel habits and alterations in the frequency as well as the consistency of stool. At present, IBS is considered as a disease of gut-brain interaction, and an increasing number of studies are focusing on the brain-gut axis. However, the brain regions associated with IBS have not been fully studied yet. In this study, we utilized the chronic restraint stress (CRS) model to evoke IBS-like symptoms in mice, which were accompanied by anxiety-like behaviors and hyperalgesia. Through cFOS staining, we observed the activation of the lateral periaqueductal gray (LPAG) in the mice after CRS. By inhibiting the activity of the LPAG through tetanus toxin or chemogenetics, we found that IBS-like symptoms could be relieved, whereas chemogenetic activation of the LPAG induced IBS-like symptoms. Finally, we utilized the classic analgesic drug sufentanil and found that it could alleviate CRS-induced IBS-like symptoms.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106758"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786225","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106763
Jinru Cui , Heli Li , Cong Hu , Feiyan Zhang , Yunjie Li , Ying Weng , Liping Yang , Yingying Li , Minglan Yao , Hao Li , Xiaoping Luo , Yan Hao
Background
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high social burden and limited treatments. Hypoxic condition of the brain is considered an important pathological mechanism of ASD. HIF1A is a key participant in brain hypoxia, but its contribution to the pathophysiological landscape of ASD remains unclear.
Methods
ASD-related datasets were obtained from GEO database, and HIF1A-related genes from GeneCards. Co-expression module analysis identified module genes, which were intersected with HIF1A-related genes to identify common genes. Machine learning identified hub genes from intersection genes and PPI networks were constructed to explore relationships among hub and HIF1A. Single-cell RNA sequencing analyzed hub gene distribution across cell clusters. ASD mouse model was created by inducing maternal immune activation (MIA) with poly(I:C) injections, verified through behavioral tests. Validation of HIF1A pathway and hub genes was confirmed through Western Blot, qPCR, and immunofluorescence in ASD mice and microglia BV-2 cells.
Results
Using CEMiTool and GeneCards, 45 genes associated with ASD and HIF1A pathway were identified. Machine learning identified CDKN1A, ETS2, LYN, and SLC16A3 as potential ASD diagnostic markers. Single-cell sequencing pinpointed activated microglia as key immune cells. Behavioral tests showed MIA offspring mice exhibited typical ASD-like behaviors. Immunofluorescence confirmed the activation of microglia and HIF1A pathway in frontal cortex of ASD mice. Additionally, IL-6 contributed to ASD by activating JUN/HIF1A pathway, affecting CDKN1A, LYN, and SLC16A3 expression in microglia.
Conclusions
HIF1A-related genes CDKN1A, ETS2, LYN, and SLC16A3 are strong diagnostic markers for ASD and the activation of IL-6/JUN/HIF1A pathway in microglia contributes to the pathogenesis of ASD.
{"title":"Unraveling pathogenesis and potential biomarkers for autism spectrum disorder associated with HIF1A pathway based on machine learning and experiment validation","authors":"Jinru Cui , Heli Li , Cong Hu , Feiyan Zhang , Yunjie Li , Ying Weng , Liping Yang , Yingying Li , Minglan Yao , Hao Li , Xiaoping Luo , Yan Hao","doi":"10.1016/j.nbd.2024.106763","DOIUrl":"10.1016/j.nbd.2024.106763","url":null,"abstract":"<div><h3>Background</h3><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high social burden and limited treatments. Hypoxic condition of the brain is considered an important pathological mechanism of ASD. HIF1A is a key participant in brain hypoxia, but its contribution to the pathophysiological landscape of ASD remains unclear.</div></div><div><h3>Methods</h3><div>ASD-related datasets were obtained from GEO database, and HIF1A-related genes from GeneCards. Co-expression module analysis identified module genes, which were intersected with HIF1A-related genes to identify common genes. Machine learning identified hub genes from intersection genes and PPI networks were constructed to explore relationships among hub and HIF1A. Single-cell RNA sequencing analyzed hub gene distribution across cell clusters. ASD mouse model was created by inducing maternal immune activation (MIA) with poly(I:C) injections, verified through behavioral tests. Validation of HIF1A pathway and hub genes was confirmed through Western Blot, qPCR, and immunofluorescence in ASD mice and microglia BV-2 cells.</div></div><div><h3>Results</h3><div>Using CEMiTool and GeneCards, 45 genes associated with ASD and HIF1A pathway were identified. Machine learning identified CDKN1A, ETS2, LYN, and SLC16A3 as potential ASD diagnostic markers. Single-cell sequencing pinpointed activated microglia as key immune cells. Behavioral tests showed MIA offspring mice exhibited typical ASD-like behaviors. Immunofluorescence confirmed the activation of microglia and HIF1A pathway in frontal cortex of ASD mice. Additionally, IL-6 contributed to ASD by activating JUN/HIF1A pathway, affecting CDKN1A, LYN, and SLC16A3 expression in microglia.</div></div><div><h3>Conclusions</h3><div>HIF1A-related genes CDKN1A, ETS2, LYN, and SLC16A3 are strong diagnostic markers for ASD and the activation of IL-6/JUN/HIF1A pathway in microglia contributes to the pathogenesis of ASD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106763"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807113","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}
Pub Date : 2025-01-01DOI: 10.1016/j.nbd.2024.106761
Maj Schneider Thomsen , Serhii Kostrikov , Lisa Greve Routhe , Kasper Bendix Johnsen , Steinunn Sara Helgudóttir , Johann Mar Gudbergsson , Thomas Lars Andresen , Torben Moos
Chronic neurodegenerative diseases are characterized by substantial inflammation with putative impairment of the brain vasculature also commonly observed. To address effects of chronic neurodegeneration on the regional vasculature under experimentally controlled circumstances, the glutamate receptor agonist ibotenic acid was injected into striatum of adult rats, which causes excitotoxicity in the substantia nigra pars reticulata (SNpr) due to imbalance between inhibitory inputs from the striatum and excitatory signals from the subthalamic nucleus. Brains were examined at 28 days (short-term neurodegeneration) and 91 days (long-term neurodegeneration) and analyzed for vascular remodeling taking both 2D and 3D approaches, the latter involving confocal microscopy of optically cleared samples combined with machine learning-based image analysis. Crysectioned and microdissected samples were analyzed for protein and gene expression respectively. The resulting neurodegeneration was accompanied by regional tissue loss and inflammation. The 3D analysis of the degenerating SNpr revealed substantial changes of the vasculature with higher density, increased diameter, and number of tortuous vessels already after 28 days, evidently continuing at 91 days. Interestingly, the vascular remodeling changes occurred without changes in the expression of endothelial tight junction proteins, vascular basement membrane proteins, or markers of angiogenesis. We propose that remodeling of the vasculature in neurodegeneration occurs due to regional tissue atrophy, which leaves the vasculature operating but prone to additional pathologies.
{"title":"Remodeling of the brain angioarchitecture in experimental chronic neurodegeneration","authors":"Maj Schneider Thomsen , Serhii Kostrikov , Lisa Greve Routhe , Kasper Bendix Johnsen , Steinunn Sara Helgudóttir , Johann Mar Gudbergsson , Thomas Lars Andresen , Torben Moos","doi":"10.1016/j.nbd.2024.106761","DOIUrl":"10.1016/j.nbd.2024.106761","url":null,"abstract":"<div><div>Chronic neurodegenerative diseases are characterized by substantial inflammation with putative impairment of the brain vasculature also commonly observed. To address effects of chronic neurodegeneration on the regional vasculature under experimentally controlled circumstances, the glutamate receptor agonist ibotenic acid was injected into striatum of adult rats, which causes excitotoxicity in the substantia nigra pars reticulata (SNpr) due to imbalance between inhibitory inputs from the striatum and excitatory signals from the subthalamic nucleus. Brains were examined at 28 days (short-term neurodegeneration) and 91 days (long-term neurodegeneration) and analyzed for vascular remodeling taking both 2D and 3D approaches, the latter involving confocal microscopy of optically cleared samples combined with machine learning-based image analysis. Crysectioned and microdissected samples were analyzed for protein and gene expression respectively. The resulting neurodegeneration was accompanied by regional tissue loss and inflammation. The 3D analysis of the degenerating SNpr revealed substantial changes of the vasculature with higher density, increased diameter, and number of tortuous vessels already after 28 days, evidently continuing at 91 days. Interestingly, the vascular remodeling changes occurred without changes in the expression of endothelial tight junction proteins, vascular basement membrane proteins, or markers of angiogenesis. We propose that remodeling of the vasculature in neurodegeneration occurs due to regional tissue atrophy, which leaves the vasculature operating but prone to additional pathologies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"204 ","pages":"Article 106761"},"PeriodicalIF":5.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813702","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}
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