Pub Date : 2024-09-18DOI: 10.1038/s41593-024-01753-w
Nils Korte, Anna Barkaway, Jack Wells, Felipe Freitas, Huma Sethi, Stephen P. Andrews, John Skidmore, Beth Stevens, David Attwell
Early in Alzheimer’s disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca2+ entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca2+]i)-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca2+]i early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD.
阿尔茨海默病(AD)早期,周细胞会收缩毛细血管,增加毛细血管的水阻力并困住免疫细胞,从而降低脑血流量(CBF)。目前还缺乏治疗方法来减弱包膜细胞介导的AD收缩。在这里,我们利用体内双光子成像激光多普勒和斑点血流测量以及磁共振成像技术,证明了通过 L 型电压门控钙通道(CaVs)进入的 Ca2+ 控制着周细胞的收缩张力。在AD模型小鼠中,我们发现整个毛细血管床的周细胞是免疫活性氧(ROS)诱发和周细胞胞内钙浓度([Ca2+]i)介导的微血管流量下降的主要驱动因素。在疾病进展早期用尼莫地平阻断钙离子通道可改善CBF,减少白细胞在周细胞体节的滞留,并减轻脑缺氧。淀粉样β(Aβ)诱发的人皮质组织周细胞收缩也因 CaV 阻断而大大减少。因此,在注意力缺失症早期降低周细胞[Ca2+]i可能是提高大脑能量供应和认知功能的一种治疗策略。
{"title":"Inhibiting Ca2+ channels in Alzheimer’s disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia","authors":"Nils Korte, Anna Barkaway, Jack Wells, Felipe Freitas, Huma Sethi, Stephen P. Andrews, John Skidmore, Beth Stevens, David Attwell","doi":"10.1038/s41593-024-01753-w","DOIUrl":"https://doi.org/10.1038/s41593-024-01753-w","url":null,"abstract":"<p>Early in Alzheimer’s disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca<sup>2+</sup> entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca<sup>2+</sup>]<sub>i</sub>)-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca<sup>2+</sup>]<sub>i</sub> early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1038/s41593-024-01757-6
Antoine Anfray, Samantha Schaeffer, Yorito Hattori, Monica M. Santisteban, Nicole Casey, Gang Wang, Michael Strickland, Ping Zhou, David M. Holtzman, Josef Anrather, Laibaik Park, Costantino Iadecola
Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer’s disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications.
{"title":"A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury","authors":"Antoine Anfray, Samantha Schaeffer, Yorito Hattori, Monica M. Santisteban, Nicole Casey, Gang Wang, Michael Strickland, Ping Zhou, David M. Holtzman, Josef Anrather, Laibaik Park, Costantino Iadecola","doi":"10.1038/s41593-024-01757-6","DOIUrl":"https://doi.org/10.1038/s41593-024-01757-6","url":null,"abstract":"<p>Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer’s disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-18DOI: 10.1038/s41593-024-01763-8
Jonathan Gallego-Rudolf, Alex I. Wiesman, Alexa Pichet Binette, Sylvia Villeneuve, Sylvain Baillet
Animal and computational models of Alzheimer’s disease (AD) indicate that early amyloid-β (Aβ) deposits drive neurons into a hyperactive regime, and that subsequent tau depositions manifest an opposite, suppressive effect as behavioral deficits emerge. Here we report analogous changes in macroscopic oscillatory neurophysiology in the human brain. We used positron emission tomography and task-free magnetoencephalography to test the effects of Aβ and tau deposition on cortical neurophysiology in 104 cognitively unimpaired older adults with a family history of sporadic AD. In these asymptomatic individuals, we found that Aβ depositions colocalize with accelerated neurophysiological activity. In those also presenting medial–temporal tau pathology, linear mixed effects of Aβ and tau depositions indicate a shift toward slower neurophysiological activity, which was also linked to cognitive decline. We conclude that early Aβ and tau depositions relate synergistically to human cortical neurophysiology and subsequent cognitive decline. Our findings provide insight into the multifaceted neurophysiological mechanisms engaged in the preclinical phases of AD.
阿尔茨海默病(AD)的动物模型和计算模型表明,早期淀粉样蛋白-β(Aβ)沉积会促使神经元进入亢奋状态,而随后的tau沉积则会随着行为障碍的出现而产生相反的抑制作用。在这里,我们报告了人脑中宏观振荡神经生理学的类似变化。我们使用正电子发射断层扫描和无任务脑磁图来测试 Aβ 和 tau 沉积对 104 名有散发性老年痴呆症家族史、认知功能未受损的老年人大脑皮层神经生理学的影响。我们发现,在这些无症状的人中,Aβ沉积与神经电生理活动的加速有共同之处。在那些同时出现内颞侧 tau 病理学的患者中,Aβ 和 tau 沉积的线性混合效应表明神经生理活动转向缓慢,这也与认知能力下降有关。我们的结论是,早期 Aβ 和 tau 沉积与人类大脑皮层神经生理学和随后的认知能力下降有协同关系。我们的研究结果让我们深入了解了多发性硬化症临床前期所涉及的多方面神经生理学机制。
{"title":"Synergistic association of Aβ and tau pathology with cortical neurophysiology and cognitive decline in asymptomatic older adults","authors":"Jonathan Gallego-Rudolf, Alex I. Wiesman, Alexa Pichet Binette, Sylvia Villeneuve, Sylvain Baillet","doi":"10.1038/s41593-024-01763-8","DOIUrl":"https://doi.org/10.1038/s41593-024-01763-8","url":null,"abstract":"<p>Animal and computational models of Alzheimer’s disease (AD) indicate that early amyloid-β (Aβ) deposits drive neurons into a hyperactive regime, and that subsequent tau depositions manifest an opposite, suppressive effect as behavioral deficits emerge. Here we report analogous changes in macroscopic oscillatory neurophysiology in the human brain. We used positron emission tomography and task-free magnetoencephalography to test the effects of Aβ and tau deposition on cortical neurophysiology in 104 cognitively unimpaired older adults with a family history of sporadic AD. In these asymptomatic individuals, we found that Aβ depositions colocalize with accelerated neurophysiological activity. In those also presenting medial–temporal tau pathology, linear mixed effects of Aβ and tau depositions indicate a shift toward slower neurophysiological activity, which was also linked to cognitive decline. We conclude that early Aβ and tau depositions relate synergistically to human cortical neurophysiology and subsequent cognitive decline. Our findings provide insight into the multifaceted neurophysiological mechanisms engaged in the preclinical phases of AD.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1038/s41593-024-01758-5
W. Jeffrey Johnston, Justin M. Fine, Seng Bum Michael Yoo, R. Becket Ebitz, Benjamin Y. Hayden
When choosing between options, we must associate their values with the actions needed to select them. We hypothesize that the brain solves this binding problem through neural population subspaces. Here, in macaques performing a choice task, we show that neural populations in five reward-sensitive regions encode the values of offers presented on the left and right in distinct subspaces. This encoding is sufficient to bind offer values to their locations while preserving abstract value information. After offer presentation, all areas encode the value of the first and second offers in orthogonal subspaces; this orthogonalization also affords binding. Our binding-by-subspace hypothesis makes two new predictions confirmed by the data. First, behavioral errors should correlate with spatial, but not temporal, neural misbinding. Second, behavioral errors should increase when offers have low or high values, compared to medium values, even when controlling for value difference. Together, these results support the idea that the brain uses semi-orthogonal subspaces to bind features.
{"title":"Semi-orthogonal subspaces for value mediate a binding and generalization trade-off","authors":"W. Jeffrey Johnston, Justin M. Fine, Seng Bum Michael Yoo, R. Becket Ebitz, Benjamin Y. Hayden","doi":"10.1038/s41593-024-01758-5","DOIUrl":"https://doi.org/10.1038/s41593-024-01758-5","url":null,"abstract":"<p>When choosing between options, we must associate their values with the actions needed to select them. We hypothesize that the brain solves this binding problem through neural population subspaces. Here, in macaques performing a choice task, we show that neural populations in five reward-sensitive regions encode the values of offers presented on the left and right in distinct subspaces. This encoding is sufficient to bind offer values to their locations while preserving abstract value information. After offer presentation, all areas encode the value of the first and second offers in orthogonal subspaces; this orthogonalization also affords binding. Our binding-by-subspace hypothesis makes two new predictions confirmed by the data. First, behavioral errors should correlate with spatial, but not temporal, neural misbinding. Second, behavioral errors should increase when offers have low or high values, compared to medium values, even when controlling for value difference. Together, these results support the idea that the brain uses semi-orthogonal subspaces to bind features.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s41593-024-01755-8
Christina Grimm, Sian N. Duss, Mattia Privitera, Brandon R. Munn, Nikolaos Karalis, Stefan Frässle, Maria Wilhelm, Tommaso Patriarchi, Daniel Razansky, Nicole Wenderoth, James M. Shine, Johannes Bohacek, Valerio Zerbi
Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain’s topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC–NA system achieves a nuanced regulation of global circuit operations.
去甲肾上腺素(NA)从脑小叶位置(LC)释放,会改变整个大脑神经元网络的活动和连接,从而调节多种行为状态。NA的释放是由LC的强直性和爆发性活动介导的。然而,目标区域的功能变化是否取决于这些发射模式尚不得而知。通过在小鼠体内使用光遗传学、光度计、电生理学和功能磁共振成像技术,我们发现强直性和爆发样 LC 发射模式会引起大脑反应,而这些反应取决于它们不同的 NA 释放动态。在适度的强直性 LC 激活过程中,NA 的释放涉及与联想处理相关的区域,而爆发式刺激则使大脑偏向于感觉处理。这些激活模式在局部与增加的星形胶质细胞和抑制性活动相结合,改变了大脑的拓扑结构,使其与大脑皮层的分层组织相一致。这些发现共同揭示了 LC-NA 系统如何实现对全局电路运行的细微调节。
{"title":"Tonic and burst-like locus coeruleus stimulation distinctly shift network activity across the cortical hierarchy","authors":"Christina Grimm, Sian N. Duss, Mattia Privitera, Brandon R. Munn, Nikolaos Karalis, Stefan Frässle, Maria Wilhelm, Tommaso Patriarchi, Daniel Razansky, Nicole Wenderoth, James M. Shine, Johannes Bohacek, Valerio Zerbi","doi":"10.1038/s41593-024-01755-8","DOIUrl":"https://doi.org/10.1038/s41593-024-01755-8","url":null,"abstract":"<p>Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain’s topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC–NA system achieves a nuanced regulation of global circuit operations.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s41593-024-01741-0
Laura Pritschet, Caitlin M. Taylor, Daniela Cossio, Joshua Faskowitz, Tyler Santander, Daniel A. Handwerker, Hannah Grotzinger, Evan Layher, Elizabeth R. Chrastil, Emily G. Jacobs
Pregnancy is a period of profound hormonal and physiological changes experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation are not well studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through 2 years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, standing in contrast to increases in white matter microstructural integrity, ventricle volume and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as a comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to further explore and understand the maternal brain.
{"title":"Neuroanatomical changes observed over the course of a human pregnancy","authors":"Laura Pritschet, Caitlin M. Taylor, Daniela Cossio, Joshua Faskowitz, Tyler Santander, Daniel A. Handwerker, Hannah Grotzinger, Evan Layher, Elizabeth R. Chrastil, Emily G. Jacobs","doi":"10.1038/s41593-024-01741-0","DOIUrl":"https://doi.org/10.1038/s41593-024-01741-0","url":null,"abstract":"<p>Pregnancy is a period of profound hormonal and physiological changes experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation are not well studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through 2 years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, standing in contrast to increases in white matter microstructural integrity, ventricle volume and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as a comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to further explore and understand the maternal brain.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1038/s41593-024-01767-4
Kathleen A. Martin, Eleni S. Papadoyannis, Jennifer K. Schiavo, Saba Shokat Fadaei, Habon A. Issa, Soomin C. Song, Sofia Orrey Valencia, Nesibe Z. Temiz, Matthew J. McGinley, David A. McCormick, Robert C. Froemke
Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions.
{"title":"Vagus nerve stimulation recruits the central cholinergic system to enhance perceptual learning","authors":"Kathleen A. Martin, Eleni S. Papadoyannis, Jennifer K. Schiavo, Saba Shokat Fadaei, Habon A. Issa, Soomin C. Song, Sofia Orrey Valencia, Nesibe Z. Temiz, Matthew J. McGinley, David A. McCormick, Robert C. Froemke","doi":"10.1038/s41593-024-01767-4","DOIUrl":"https://doi.org/10.1038/s41593-024-01767-4","url":null,"abstract":"<p>Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1038/s41593-024-01754-9
Guojiao Huang, Zhidan Li, Xuezhao Liu, Menglong Guan, Songlin Zhou, Xiaowen Zhong, Tao Zheng, Dazhuan Xin, Xiaosong Gu, Dezhi Mu, Yingkun Guo, Lin Zhang, Liguo Zhang, Q. Richard Lu, Xuelian He
The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage cells. Dor ablation in mice of both sexes results in defective myelinogenesis and remyelination. Genomic occupancy in oligodendrocytes and transcriptome profiling of the optic nerves of wild-type and Dor conditional knockout mice reveal that DOR and SOX10 co-occupy enhancers of critical myelinogenesis-associated genes including Prr18, encoding an oligodendrocyte-enriched, proline-rich factor. We show that DOR targets regulatory elements of genes responsible for α-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for α-ketoglutarate production and lipid biosynthesis. Supplementation with α-ketoglutarate restores oligodendrocyte-maturation defects in Dor-deficient adult mice and improves remyelination after lysolecithin-induced demyelination and cognitive function in 17-month-old wild-type mice. Our data suggest that activation of α-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging.
成熟少突胶质细胞产生髓鞘的能力下降会对脱髓鞘疾病和衰老中的再髓鞘化产生负面影响,但其潜在机制尚不完全清楚。在本研究中,我们发现了一个成熟少突胶质细胞富集的转录核心调节因子糖尿病和肥胖相关基因(DOR)/肿瘤蛋白 p53 诱导核蛋白 2(TP53INP2),它在多发性硬化症供体的脱髓鞘病变和衰老的少突胶质细胞系细胞中下调。小鼠(雌雄均可)的髓鞘消融导致髓鞘生成和再髓鞘化缺陷。野生型小鼠和 Dor 条件性基因敲除小鼠视神经中的少突胶质细胞基因组占位和转录组图谱分析表明,DOR 和 SOX10 共同占据了关键的髓鞘生成相关基因的增强子,包括 Prr18(编码一种富含脯氨酸的少突胶质细胞因子)。我们的研究表明,DOR靶向成熟少突胶质细胞中负责α-酮戊二酸生物合成的基因的调控元件,并且对α-酮戊二酸的产生和脂质的生物合成至关重要。补充α-酮戊二酸可恢复Dor缺陷成年小鼠少突胶质细胞成熟缺陷,并改善溶血卵磷脂诱导脱髓鞘后的再髓鞘化和17个月大野生型小鼠的认知功能。我们的数据表明,激活成熟少突胶质细胞中的α-酮戊二酸代谢可促进脱髓鞘和衰老过程中的髓鞘生成。
{"title":"DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice","authors":"Guojiao Huang, Zhidan Li, Xuezhao Liu, Menglong Guan, Songlin Zhou, Xiaowen Zhong, Tao Zheng, Dazhuan Xin, Xiaosong Gu, Dezhi Mu, Yingkun Guo, Lin Zhang, Liguo Zhang, Q. Richard Lu, Xuelian He","doi":"10.1038/s41593-024-01754-9","DOIUrl":"https://doi.org/10.1038/s41593-024-01754-9","url":null,"abstract":"<p>The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage cells. <i>Dor</i> ablation in mice of both sexes results in defective myelinogenesis and remyelination. Genomic occupancy in oligodendrocytes and transcriptome profiling of the optic nerves of wild-type and <i>Dor</i> conditional knockout mice reveal that DOR and SOX10 co-occupy enhancers of critical myelinogenesis-associated genes including <i>Prr18</i>, encoding an oligodendrocyte-enriched, proline-rich factor. We show that DOR targets regulatory elements of genes responsible for α-ketoglutarate biosynthesis in mature oligodendrocytes and is essential for α-ketoglutarate production and lipid biosynthesis. Supplementation with α-ketoglutarate restores oligodendrocyte-maturation defects in <i>Dor</i>-deficient adult mice and improves remyelination after lysolecithin-induced demyelination and cognitive function in 17-month-old wild-type mice. Our data suggest that activation of α-ketoglutarate metabolism in mature oligodendrocytes can promote myelin production during demyelination and aging.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-12DOI: 10.1038/s41593-024-01750-z
We reveal that lipid turnover in the myelin sheath generates a fatty acid pool in oligodendrocytes that can contribute to the energy balance of white matter tracts. We also demonstrate that when glucose levels are limiting, fatty acid metabolism can support glial cell survival and the basic functional integrity of myelinated axons.
{"title":"Myelin lipid metabolism can provide energy for starved axons","authors":"","doi":"10.1038/s41593-024-01750-z","DOIUrl":"https://doi.org/10.1038/s41593-024-01750-z","url":null,"abstract":"We reveal that lipid turnover in the myelin sheath generates a fatty acid pool in oligodendrocytes that can contribute to the energy balance of white matter tracts. We also demonstrate that when glucose levels are limiting, fatty acid metabolism can support glial cell survival and the basic functional integrity of myelinated axons.","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1038/s41593-024-01746-9
Sanjid Shahriar, Saptarshi Biswas, Kaitao Zhao, Uğur Akcan, Mary Claire Tuohy, Michael D. Glendinning, Ali Kurt, Charlotte R. Wayne, Grace Prochilo, Maxwell Z. Price, Heidi Stuhlmann, Rolf A. Brekken, Vilas Menon, Dritan Agalliu
Newly formed leaky vessels and blood–brain barrier (BBB) damage are present in demyelinating acute and chronic lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the endothelial cell subtypes and signaling pathways contributing to these leaky neovessels are unclear. Here, using single-cell transcriptional profiling and in vivo validation studies, we show that venous endothelial cells express neoangiogenesis gene signatures and show increased proliferation resulting in enlarged veins and higher venous coverage in acute and chronic EAE lesions in female adult mice. These changes correlate with the upregulation of vascular endothelial growth factor A (VEGF-A) signaling. We also confirmed increased expression of neoangiogenic markers in acute and chronic human MS lesions. Treatment with a VEGF-A blocking antibody diminishes the neoangiogenic transcriptomic signatures and vascular proliferation in female adult mice with EAE, but it does not restore BBB function or ameliorate EAE pathology. Our data demonstrate that venous endothelial cells contribute to neoangiogenesis in demyelinating neuroinflammatory conditions.
{"title":"VEGF-A-mediated venous endothelial cell proliferation results in neoangiogenesis during neuroinflammation","authors":"Sanjid Shahriar, Saptarshi Biswas, Kaitao Zhao, Uğur Akcan, Mary Claire Tuohy, Michael D. Glendinning, Ali Kurt, Charlotte R. Wayne, Grace Prochilo, Maxwell Z. Price, Heidi Stuhlmann, Rolf A. Brekken, Vilas Menon, Dritan Agalliu","doi":"10.1038/s41593-024-01746-9","DOIUrl":"https://doi.org/10.1038/s41593-024-01746-9","url":null,"abstract":"<p>Newly formed leaky vessels and blood–brain barrier (BBB) damage are present in demyelinating acute and chronic lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the endothelial cell subtypes and signaling pathways contributing to these leaky neovessels are unclear. Here, using single-cell transcriptional profiling and in vivo validation studies, we show that venous endothelial cells express neoangiogenesis gene signatures and show increased proliferation resulting in enlarged veins and higher venous coverage in acute and chronic EAE lesions in female adult mice. These changes correlate with the upregulation of vascular endothelial growth factor A (VEGF-A) signaling. We also confirmed increased expression of neoangiogenic markers in acute and chronic human MS lesions. Treatment with a VEGF-A blocking antibody diminishes the neoangiogenic transcriptomic signatures and vascular proliferation in female adult mice with EAE, but it does not restore BBB function or ameliorate EAE pathology. Our data demonstrate that venous endothelial cells contribute to neoangiogenesis in demyelinating neuroinflammatory conditions.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":null,"pages":null},"PeriodicalIF":25.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}