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NX210c drug candidate peptide strengthens mouse and human blood-brain barriers. NX210c 候选药物肽能增强小鼠和人类的血脑屏障。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-27 DOI: 10.1186/s12987-024-00577-x
Chris Greene, Nicolas Rebergue, Gwen Fewell, Damir Janigro, Yann Godfrin, Matthew Campbell, Sighild Lemarchant

Background: Alterations of blood-brain barrier (BBB) and blood-spinal cord barrier have been documented in various animal models of neurodegenerative diseases and in patients. Correlations of these alterations with functional deficits suggest that repairing barriers integrity may represent a disease-modifying approach to prevent neuroinflammation and neurodegeneration induced by the extravasation of blood components into the parenchyma. Here, we screened the effect of a subcommissural organ-spondin-derived peptide (NX210c), known to promote functional recovery in several models of neurological disorders, on BBB integrity in vitro and in vivo.

Methods: In vitro, bEnd.3 endothelial cell (EC) monolayers and two different primary human BBB models containing EC, astrocytes and pericytes, in static and microfluidic conditions, were treated with NX210c (1-100 µM), or its vehicle, for 4 h and up to 5 days. Tight junction (TJ) protein levels, permeability to dextrans and transendothelial electrical resistance (TEER) were evaluated. In vivo, young and old mice (3- and 21-month-old, respectively) were treated daily intraperitoneally with NX210c at 10 mg/kg or its vehicle for 5 days and their brains collected at day 6 to measure TJ protein levels by immunohistochemistry.

Results: NX210c induced an increase in claudin-5 protein expression after 24-h and 72-h treatments in mouse EC. Occludin level was also increased after a 24-h treatment. Accordingly, NX210c decreased by half the permeability of EC to a 40-kDa FITC-dextran and increased TEER. In the human static BBB model, NX210c increased by ∼ 25% the TEER from 3 to 5 days. NX210c also increased TEER in the human 3D dynamic BBB model after 4 h, which was associated with a reduced permeability to a 4-kDa FITC-dextran. In line with in vitro results, after only 5 days of daily treatments in mice, NX210c restored aging-induced reduction of claudin-5 and occludin levels in the hippocampus, and also in the cortex for occludin.

Conclusions: In summary, we have gathered preclinical data showing the capacity of NX210c to strengthen BBB integrity. Through this property, NX210c holds great promises of being a disease-modifying treatment for several neurological disorders with high unmet medical needs.

背景:血脑屏障(BBB)和血脊髓屏障的改变已在各种神经退行性疾病动物模型和患者中得到证实。这些改变与功能缺陷的相关性表明,修复屏障的完整性可能是防止血液成分外渗到实质组织所诱发的神经炎症和神经变性的一种疾病调节方法。在此,我们筛选了一种来源于软骨下器官的多肽(NX210c)对体外和体内 BBB 完整性的影响:方法:在体外,在静态和微流体条件下,用 NX210c(1-100 µM)或其载体处理 bEnd.3 内皮细胞(EC)单层和两种不同的原发性人 BBB 模型(包含 EC、星形胶质细胞和周细胞)4 小时和长达 5 天。对紧密连接(TJ)蛋白水平、右旋糖酐通透性和跨内皮电阻(TEER)进行了评估。在体内,年轻和年老的小鼠(分别为 3 个月和 21 个月大)每天腹腔注射 10 毫克/千克的 NX210c 或其载体,共注射 5 天,在第 6 天收集它们的大脑,用免疫组化法测定 TJ 蛋白水平:结果:NX210c处理小鼠EC 24小时和72小时后,诱导claudin-5蛋白表达增加。经过 24 小时处理后,闭塞素水平也有所增加。因此,NX210c 可使小鼠心肌对 40-kDa FITC-葡聚糖的通透性降低一半,并增加 TEER。在人体静态 BBB 模型中,从 3 天到 5 天,NX210c 可使 TEER 增加 25%。4 小时后,NX210c 还能增加人体三维动态 BBB 模型的 TEER,这与 4 kDa FITC-葡聚糖通透性降低有关。与体外实验结果一致的是,小鼠每天服用 5 天后,NX210c 就能恢复老化引起的海马中 claudin-5 和 occludin 水平的降低,同时也能恢复皮层中 occludin 水平的降低:总之,我们收集的临床前数据显示,NX210c 有能力加强 BBB 的完整性。通过这一特性,NX210c 很有希望成为治疗多种神经系统疾病的疾病调节剂,这些疾病的医疗需求尚未得到满足。
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引用次数: 0
Truncated mini LRP1 transports cargo from luminal to basolateral side across the blood brain barrier 截短的迷你 LRP1 将货物从管腔转运至基底侧,穿越血脑屏障
IF 7.3 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-17 DOI: 10.1186/s12987-024-00573-1
Laura Fritzen, Katharina Wienken, Lelia Wagner, Magdalena Kurtyka, Katharina Vogel, Jakob Körbelin, Sascha Weggen, Gert Fricker, Claus U. Pietrzik
The most crucial area to focus on when thinking of novel pathways for drug delivery into the CNS is the blood brain barrier (BBB). A number of nanoparticulate formulations have been shown in earlier research to target receptors at the BBB and transport therapeutics into the CNS. However, no mechanism for CNS entrance and movement throughout the CNS parenchyma has been proposed yet. Here, the truncated mini low-density lipoprotein receptor-related protein 1 mLRP1_DIV* was presented as blood to brain transport carrier, exemplified by antibodies and immunoliposomes using a systematic approach to screen the receptor and its ligands’ route across endothelial cells in vitro. The use of mLRP1_DIV* as liposomal carrier into the CNS was validated based on internalization and transport assays across an in vitro model of the BBB using hcMEC/D3 and bEnd.3 cells. Trafficking routes of mLRP1_DIV* and corresponding cargo across endothelial cells were analyzed using immunofluorescence. Modulation of γ-secretase activity by immunoliposomes loaded with the γ-secretase modulator BB25 was investigated in co-cultures of bEnd.3 mLRP1_DIV* cells and CHO cells overexpressing human amyloid precursor protein (APP) and presenilin 1 (PSEN1). We showed that while expressed in vitro, mLRP1_DIV* transports both, antibodies and functionalized immunoliposomes from luminal to basolateral side across an in vitro model of the BBB, followed by their mLRP1_DIV* dependent release of the cargo. Importantly, functionalized liposomes loaded with the γ-secretase modulator BB25 were demonstrated to effectively reduce toxic Aß42 peptide levels after mLRP1_DIV* mediated transport across a co-cultured endothelial monolayer. Together, the data strongly suggest mLRP1_DIV* as a promising tool for drug delivery into the CNS, as it allows a straight transport of cargo from luminal to abluminal side across an endothelial monolayer and it’s release into brain parenchyma in vitro, where it exhibits its intended therapeutic effect.
在考虑向中枢神经系统输送药物的新途径时,最关键的领域是脑血屏障(BBB)。早期研究表明,许多纳米颗粒制剂都能靶向 BBB 的受体,将治疗药物输送到中枢神经系统。然而,目前还没有提出中枢神经系统入口和在中枢神经系统实质内移动的机制。在这里,研究人员提出了截短的迷你低密度脂蛋白受体相关蛋白1 mLRP1_DIV*作为血液到大脑的转运载体,以抗体和免疫脂质体为例,采用系统的方法在体外筛选受体及其配体穿过内皮细胞的路线。通过使用 hcMEC/D3 和 bEnd.3 细胞在 BBB 体外模型中进行内化和运输试验,验证了 mLRP1_DIV* 作为脂质体载体进入中枢神经系统的有效性。使用免疫荧光分析了 mLRP1_DIV* 和相应货物通过内皮细胞的运输路线。在bEnd.3 mLRP1_DIV*细胞和过表达人淀粉样前体蛋白(APP)和预淀粉样蛋白1(PSEN1)的CHO细胞的共培养物中,研究了装载有γ-分泌酶调节剂BB25的免疫脂质体对γ-分泌酶活性的调节作用。我们的研究表明,在体外表达时,mLRP1_DIV*能将抗体和功能化免疫脂质体从管腔转运到基底侧,穿过体外的 BBB 模型,然后依赖 mLRP1_DIV* 释放货物。重要的是,在 mLRP1_DIV* 介导的跨共培养内皮单层运输过程中,负载有 γ 分泌酶调节剂 BB25 的功能化脂质体被证明能有效降低毒性 Aß42 肽的水平。总之,这些数据有力地表明,mLRP1_DIV* 是一种很有前景的向中枢神经系统递送药物的工具,因为它能使货物从管腔侧直接运输到管腔侧,穿过内皮单层,并在体外释放到脑实质中,在脑实质中显示出预期的治疗效果。
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引用次数: 0
Commentary on “Transient intracranial pressure elevations (B waves) associated with sleep apnea”: the neglected role of cyclic alternating pattern 关于 "与睡眠呼吸暂停相关的一过性颅内压升高(B 波)"的评论:被忽视的周期性交替模式的作用
IF 7.3 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-17 DOI: 10.1186/s12987-024-00569-x
Carlotta Mutti, Clara Rapina, Francesco Rausa, Giulia Balella, Dario Bottignole, Marcello Giuseppe Maggio, Liborio Parrino
<p>Riedel et al. recently published an interesting paper on the association between intracranial pressure (ICP) elevation, measured through the Lundberg B waves, and sleep apnea in a group of patients with idiopathic intracranial hypertension (IIH) and hydrocephalus [1].</p><p>ICP B waves are defined as short, repetitive elevation of intracranial pressure of up to 50 mmHg with a frequency of 0.5-2 waves/min, which are typically observed in patients with IIH, but can also be measured in subjects with normal intracranial pressure [2].</p><p>Obstructive sleep apnea (OSA) is a multi-systemic syndrome characterized by phasic interruptions of airflow during sleep, leading to severe sleep fragmentation and cardiovascular consequences, presenting a typical 20-40 s periodicity (Panel A, Fig. 1).</p><figure><figcaption><b data-test="figure-caption-text">Fig. 1</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png?as=webp" type="image/webp"/><img alt="figure 1" aria-describedby="Fig1" height="383" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png" width="685"/></picture><p><b>A</b> Vertical integration between CAP fluctuations during NREM sleep, respiratory events, oxygen desaturation and pulse rate dynamic in a patient affected by OSA. <b>B</b> figure published in Riedel et al., 2023 showing the vertical integration between ICP oscillations, obstructive apnea events and sleep fragmentation. <b>C</b> example of physiological CAP fluctuations during NREM sleep in a healthy subject. <b>D</b> example of stable NREM with no CAP intrusion</p><span>Full size image</span><svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-chevron-right-small" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></figure><p>According to Riedel et al. [1], there is an interesting association between ICP B waves and sleep apnea. The overlap of B waves with repetitive respiratory events induces a further increase in the ICP elevation (See Panel B in Fig. 1). The synusoidal pattern becomes particularly relevant during obstructive respiratory events (compared to central-type events), whereas the introduction of CPAP leads to overall reduction of phasic ICP elevations.</p><p>Riedel et al. [1] show the temporal coupling between ICP fluctuations, nasal airflow flattening, thorax and abdomen activity changes, SatO2% oscillations and sleep stage dynamics.</p><p>In Panel B (Fig. 1) severe sleep fragmentation characterized by numerous brief awakening lasting < 2 min is recognizable in a patient with idiopathic normal pressure hydrocephalus and OSA during stage N2 of NREM sleep.</p><p>It is known that OSA is closely associated cyclic alternating pattern (CAP) oscillations, including not only fast but also slow-wave arous
Riedel 等人最近发表了一篇有趣的论文,研究了一组特发性颅内高压(IIH)和脑积水患者的颅内压(ICP)升高(通过伦德伯格 B 波测量)与睡眠呼吸暂停之间的关系[1]。ICP B 波是指颅内压短时、重复性升高,最高可达 50 mmHg,频率为 0.5-2 波/分钟,通常在 IIH 患者中观察到,但也可在颅内压正常的受试者中测量到[2]。阻塞性睡眠呼吸暂停(OSA)是一种多系统综合征,其特点是睡眠期间气流的阶段性中断,导致严重的睡眠破碎和心血管后果,呈现典型的 20-40 秒周期性(图 1,A 组)。B 图发表于 Riedel 等人,2023 年,显示了 ICP 振荡、阻塞性呼吸暂停事件和睡眠片段之间的垂直整合。C 健康人 NREM 睡眠期间 CAP 生理波动示例。根据 Riedel 等人的研究[1],ICP B 波与睡眠呼吸暂停之间存在有趣的联系。B 波与重复呼吸事件重叠会导致 ICP 进一步升高(见图 1 中的 B 小组)。Riedel 等人[1] 显示了 ICP 波动、鼻气流平缓、胸腹活动变化、SatO2% 振荡和睡眠阶段动态之间的时间耦合。众所周知,OSA 与周期性交替模式(CAP)振荡密切相关,不仅包括快波唤醒,还包括慢波唤醒[3],与正在发生的睡眠呼吸紊乱的严重程度密切相关[4]。CAP 是睡眠不稳定性的电生理生物标记,在 NREM 睡眠期间周期性地干扰脑电图背景(C 小组)。值得注意的是,CAP 与伦德伯格 B 波的时域完全相同,从 2 秒到 60 秒不等,突破了睡眠评分 30 秒的硬性界限。NREM 睡眠期间剩余的静止脑电图活动被描述为非 CAP 睡眠(图 1,D 小组)。我们认为,CAP 指标更能反映 Lundberg B 波与 OSA 依赖性睡眠支离破碎之间的关联,而不是简短的觉醒或唤醒。Riedel 等人[1]的研究表明,在研究的 OSA 患者群中,CPAP 会显著改变 Lundberg B 波。这些发现可能解释了为什么在快速眼动睡眠中 ICP 波动会部分丧失清晰的振荡模式,因为众所周知,CAP 生理上只发生在快速眼动睡眠中[7].无论处于哪个睡眠阶段,快速眼动睡眠都可以被描述为稳定(非 CAP)和不稳定(CAP)交替的双峰大脑状态(分别见图 1 中的面板 C 和面板 D)。垂直整合 "方法包括脑电图以外的特征(如心肺耦合、行为变化,或许还包括颅内 B 波),可能是研究 NREM 睡眠期间所有振荡的最适当方法[8]。据我们所知,探索 ICP 升高与 CAP 之间联系的研究从未进行过。Riedel CS, Martinez-Tejada I, Andresen M, Wilhjelm JE, Jennum P, Juhler M. Transient intracranial pressure elevations (B waves) are associated with sleep apnea.Fluids Barriers CNS.2023;20(1):69. https://doi.org/10.1186/s12987-023-00469-6.Article PubMed PubMed Central Google Scholar Riedel CS, Martinez-Tejada I, Norager NH, Kempfner L, Jennum P, Juhler M. B波存在于无颅内压紊乱的患者中。J Sleep Res. 2021;30(4): e13214. https://doi.org/10.1111/jsr.13214.Article PubMed Google Scholar Milioli G, Bosi M, Grassi A, et al. Can sleep microstructure improve diagnosis of OSAS? integrative information from CAP parameters.2015;153(2-3):194-203. https://doi.org/10.12871/0003982920152344.
{"title":"Commentary on “Transient intracranial pressure elevations (B waves) associated with sleep apnea”: the neglected role of cyclic alternating pattern","authors":"Carlotta Mutti, Clara Rapina, Francesco Rausa, Giulia Balella, Dario Bottignole, Marcello Giuseppe Maggio, Liborio Parrino","doi":"10.1186/s12987-024-00569-x","DOIUrl":"https://doi.org/10.1186/s12987-024-00569-x","url":null,"abstract":"&lt;p&gt;Riedel et al. recently published an interesting paper on the association between intracranial pressure (ICP) elevation, measured through the Lundberg B waves, and sleep apnea in a group of patients with idiopathic intracranial hypertension (IIH) and hydrocephalus [1].&lt;/p&gt;&lt;p&gt;ICP B waves are defined as short, repetitive elevation of intracranial pressure of up to 50 mmHg with a frequency of 0.5-2 waves/min, which are typically observed in patients with IIH, but can also be measured in subjects with normal intracranial pressure [2].&lt;/p&gt;&lt;p&gt;Obstructive sleep apnea (OSA) is a multi-systemic syndrome characterized by phasic interruptions of airflow during sleep, leading to severe sleep fragmentation and cardiovascular consequences, presenting a typical 20-40 s periodicity (Panel A, Fig. 1).&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaption&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"383\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12987-024-00569-x/MediaObjects/12987_2024_569_Fig1_HTML.png\" width=\"685\"/&gt;&lt;/picture&gt;&lt;p&gt;&lt;b&gt;A&lt;/b&gt; Vertical integration between CAP fluctuations during NREM sleep, respiratory events, oxygen desaturation and pulse rate dynamic in a patient affected by OSA. &lt;b&gt;B&lt;/b&gt; figure published in Riedel et al., 2023 showing the vertical integration between ICP oscillations, obstructive apnea events and sleep fragmentation. &lt;b&gt;C&lt;/b&gt; example of physiological CAP fluctuations during NREM sleep in a healthy subject. &lt;b&gt;D&lt;/b&gt; example of stable NREM with no CAP intrusion&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;According to Riedel et al. [1], there is an interesting association between ICP B waves and sleep apnea. The overlap of B waves with repetitive respiratory events induces a further increase in the ICP elevation (See Panel B in Fig. 1). The synusoidal pattern becomes particularly relevant during obstructive respiratory events (compared to central-type events), whereas the introduction of CPAP leads to overall reduction of phasic ICP elevations.&lt;/p&gt;&lt;p&gt;Riedel et al. [1] show the temporal coupling between ICP fluctuations, nasal airflow flattening, thorax and abdomen activity changes, SatO2% oscillations and sleep stage dynamics.&lt;/p&gt;&lt;p&gt;In Panel B (Fig. 1) severe sleep fragmentation characterized by numerous brief awakening lasting &lt; 2 min is recognizable in a patient with idiopathic normal pressure hydrocephalus and OSA during stage N2 of NREM sleep.&lt;/p&gt;&lt;p&gt;It is known that OSA is closely associated cyclic alternating pattern (CAP) oscillations, including not only fast but also slow-wave arous","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256275","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}
引用次数: 0
Blood–brain barrier breakdown in dementia with Lewy bodies 路易体痴呆症的血脑屏障破坏
IF 7.3 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-17 DOI: 10.1186/s12987-024-00575-z
Jinghuan Gan, Ziming Xu, Zhichao Chen, Shuai Liu, Hao Lu, Yajie Wang, Hao Wu, Zhihong Shi, Huijun Chen, Yong Ji
Blood–brain barrier (BBB) dysfunction has been viewed as a potential underlying mechanism of neurodegenerative disorders, possibly involved in the pathogenesis and progression of Alzheimer’s disease (AD). However, a relation between BBB dysfunction and dementia with Lewy bodies (DLB) has yet to be systematically investigated. Given the overlapping clinical features and neuropathology of AD and DLB, we sought to evaluate BBB permeability in the context of DLB and determine its association with plasma amyloid-β (Aβ) using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). For this prospective study, we examined healthy controls (n = 24, HC group) and patients diagnosed with AD (n = 29) or DLB (n = 20) between December 2020 and April 2022. Based on DCE-MRI studies, mean rates of contrast agent transfer from intra- to extravascular spaces (Ktrans) were calculated within regions of interest. Spearman’s correlation and multivariate linear regression were applied to analyze associations between Ktrans and specific clinical characteristics. In members of the DLB (vs HC) group, Ktrans values of cerebral cortex (p = 0.024), parietal lobe (p = 0.007), and occipital lobe (p = 0.014) were significantly higher; and Ktrans values of cerebral cortex (p = 0.041) and occipital lobe (p = 0.018) in the DLB group were significantly increased, relative to those of the AD group. All participants also showed increased Ktrans values of parietal ( $$upbeta$$ = 0.391; p = 0.001) and occipital ( $$upbeta$$ = 0.357; p = 0.002) lobes that were significantly associated with higher scores of the Clinical Dementia Rating, once adjusted for age and sex. Similarly, increased Ktrans values of cerebral cortex ( $$upbeta$$ = 0.285; p = 0.015), frontal lobe ( $$upbeta$$ = 0.237; p = 0.043), and parietal lobe ( $$upbeta$$ = 0.265; p = 0.024) were significantly linked to higher plasma Aβ1-42/Aβ1-40 ratios, after above adjustments. BBB leakage is a common feature of DLB and possibly is even more severe than in the setting of AD for certain regions of the brain. BBB leakage appears to correlate with plasma Aβ1-42/Aβ1-40 ratio and dementia severity.
血脑屏障(BBB)功能障碍一直被视为神经退行性疾病的潜在潜在机制,可能与阿尔茨海默病(AD)的发病机制和进展有关。然而,血脑屏障功能障碍与路易体痴呆(DLB)之间的关系还有待系统研究。鉴于AD和DLB的临床特征和神经病理学有重叠之处,我们试图评估DLB的BBB通透性,并使用动态对比增强磁共振成像(DCE-MRI)确定其与血浆淀粉样蛋白-β(Aβ)的关系。在这项前瞻性研究中,我们对2020年12月至2022年4月期间的健康对照组(24人,HC组)和确诊为AD(29人)或DLB(20人)的患者进行了检查。基于 DCE-MRI 研究,我们计算了相关区域内造影剂从血管内向血管外转移的平均速率(Ktrans)。斯皮尔曼相关性和多变量线性回归用于分析 Ktrans 与特定临床特征之间的关联。在DLB(vs HC)组中,大脑皮层(p = 0.024)、顶叶(p = 0.007)和枕叶(p = 0.014)的Ktrans值显著高于AD组;而在DLB组中,大脑皮层(p = 0.041)和枕叶(p = 0.018)的Ktrans值显著高于AD组。所有参与者的顶叶($$upbeta$$ = 0.391; p = 0.001)和枕叶($$upbeta$$ = 0.357; p = 0.002)的Ktrans值也显示出增加,在对年龄和性别进行调整后,这与临床痴呆评级的较高分数显著相关。同样,经上述调整后,大脑皮层($$upbeta$$ = 0.285; p = 0.015)、额叶($$upbeta$$ = 0.237; p = 0.043)和顶叶($$upbeta$$ = 0.265; p = 0.024)的Ktrans值增加与血浆Aβ1-42/Aβ1-40比率升高有显著联系。BBB 渗漏是 DLB 的常见特征,在大脑的某些区域可能比 AD 更为严重。BBB 渗漏似乎与血浆 Aβ1-42/Aβ1-40 比率和痴呆症严重程度相关。
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引用次数: 0
Rapid imaging of intravenous gadolinium-based contrast agent (GBCA) entering ventricular cerebrospinal fluid (CSF) through the choroid plexus in healthy human subjects 对健康人通过脉络丛进入脑室脑脊液(CSF)的静脉注射钆基造影剂(GBCA)进行快速成像
IF 7.3 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-16 DOI: 10.1186/s12987-024-00571-3
Yuanqi Sun, Di Cao, Jay J. Pillai, Adrian Paez, Yinghao Li, Chunming Gu, Jacob M. Pogson, Linda Knutsson, Peter B. Barker, Peter C. M. van Zijl, Arnold Bakker, Bryan K. Ward, Jun Hua
Pathways for intravenously administered gadolinium-based-contrast-agents (GBCAs) entering cerebrospinal-fluid (CSF) circulation in the human brain are not well-understood. The blood-CSF-barrier (BCSFB) in choroid-plexus (CP) has long been hypothesized to be a main entry-point for intravenous-GBCAs into CSF. Most existing studies on this topic were performed in animals and human patients with various diseases. Results in healthy human subjects are limited. Besides, most studies were performed using MRI methods with limited temporal resolution and significant partial-volume effects from blood and CSF. This study employs the recently developed dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI approach to measure GBCA-distribution in the CSF immediately and 4 h after intravenous-GBCA administration in healthy subjects. With a temporal resolution of 10 s, cDSC MRI can track GBCA-induced CSF signal changes during the bolus phase, which has not been investigated previously. It employs a long echo-time (TE = 1347 ms) to suppress tissue and blood signals so that pure CSF signal is detected with minimal partial-volume effects. GBCA concentration in the CSF can be estimated from cDSC MRI. In this study, cDSC and FLAIR MRI were performed immediately and 4 h after intravenous GBCA administration in 25 healthy volunteers (age 48.9 ± 19.5 years; 14 females). Paired t-tests were used to compare pre-GBCA and post-GBCA signal changes, and their correlations with age were evaluated using Pearson-correlation-coefficients. At ~ 20 s post-GBCA, GBCA-induced cDSC signal changes were detected in the CSF around CP (ΔS/S = − 2.40 ± 0.30%; P < .001) but not in the rest of lateral ventricle (LV). At 4 h, significant GBCA-induced cDSC signal changes were observed in the entire LV (ΔS/S = − 7.58 ± 3.90%; P = .002). FLAIR MRI showed a similar trend. GBCA-induced CSF signal changes did not correlate with age. These results provided direct imaging evidence that GBCAs can pass the BCSFB in the CP and enter ventricular CSF immediately after intravenous administration in healthy human brains. Besides, our results in healthy subjects established a basis for clinical studies in brain diseases exploiting GBCA-enhanced MRI to detect BCSFB dysfunction.
静脉注射的钆基造影剂(GBCA)进入人脑脑脊液(CSF)循环的途径尚不十分清楚。长期以来,人们一直假设脉络丛(CP)中的血-脑脊液屏障(BCSFB)是静脉注射钆基造影剂进入脑脊液的主要入口。关于这一主题的大多数现有研究都是在动物和患有各种疾病的人类患者身上进行的。针对健康人体的研究结果非常有限。此外,大多数研究都是使用核磁共振成像方法进行的,其时间分辨率有限,且血液和 CSF 的部分体积效应显著。本研究采用最近开发的动态-敏感-对比-CSF(cDSC)磁共振成像方法,测量健康受试者静脉注射 GBCA 后立即和 4 小时后 CSF 中的 GBCA 分布。cDSC MRI 的时间分辨率为 10 秒,可以跟踪 GBCA 在用药阶段引起的 CSF 信号变化,这在以前还没有进行过研究。它采用长回波时间(TE = 1347 ms)来抑制组织和血液信号,从而在检测到纯 CSF 信号的同时将部分容积效应降至最低。通过 cDSC MRI 可以估算 CSF 中的 GBCA 浓度。本研究对 25 名健康志愿者(年龄 48.9 ± 19.5 岁;14 名女性)静脉注射 GBCA 后立即和 4 小时进行了 cDSC 和 FLAIR MRI 检查。使用配对 t 检验比较 GBCA 前和 GBCA 后的信号变化,并使用 Pearson-correlation-coefficients 评估其与年龄的相关性。在 GBCA 后约 20 秒,CP 周围的 CSF 中检测到 GBCA 诱导的 cDSC 信号变化(ΔS/S = - 2.40 ± 0.30%;P < .001),但在侧脑室(LV)的其他部分未检测到。4 小时后,在整个 LV 观察到明显的 GBCA 诱导的 cDSC 信号变化(ΔS/S = - 7.58 ± 3.90%; P = .002)。FLAIR MRI 也显示出类似的趋势。GBCA 诱导的 CSF 信号变化与年龄无关。这些结果提供了直接的成像证据,证明在健康人脑中静脉给药后,GBCA 可通过 CP 中的 BCSFB 并立即进入脑室 CSF。此外,我们在健康受试者身上获得的结果为利用 GBCA 增强 MRI 检测 BCSFB 功能障碍的脑疾病临床研究奠定了基础。
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引用次数: 0
Coupled pulsatile vascular and paravascular fluid dynamics in the human brain 人脑中的搏动血管和血管旁流体耦合动力学
IF 7.3 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-11 DOI: 10.1186/s12987-024-00572-2
Adam M. Wright, Yu-Chien Wu, Ho-Ching Yang, Shannon L. Risacher, Andrew J. Saykin, Yunjie Tong, Qiuting Wen
Cardiac pulsation propels blood through the cerebrovascular network to maintain cerebral homeostasis. The cerebrovascular network is uniquely surrounded by paravascular cerebrospinal fluid (pCSF), which plays a crucial role in waste removal, and its flow is suspected to be driven by arterial pulsations. Despite its importance, the relationship between vascular and paravascular fluid dynamics throughout the cardiac cycle remains poorly understood in humans. In this study, we developed a non-invasive neuroimaging approach to investigate the coupling between pulsatile vascular and pCSF dynamics within the subarachnoid space of the human brain. Resting-state functional MRI (fMRI) and dynamic diffusion-weighted imaging (dynDWI) were retrospectively cardiac-aligned to represent cerebral hemodynamics and pCSF motion, respectively. We measured the time between peaks (∆TTP) in $$frac{d}{dphi }fMRI$$ and dynDWI waveforms and measured their coupling by calculating the waveforms correlation after peak alignment (correlation at aligned peaks). We compared the ∆TTP and correlation at aligned peaks between younger [mean age: 27.9 (3.3) years, n = 9] and older adults [mean age: 70.5 (6.6) years, n = 20], and assessed their reproducibility within subjects and across different imaging protocols. Hemodynamic changes consistently precede pCSF motion. ∆TTP was significantly shorter in younger adults compared to older adults (−0.015 vs. −0.069, p < 0.05). The correlation at aligned peaks were high and did not differ between younger and older adults (0.833 vs. 0.776, p = 0.153). The ∆TTP and correlation at aligned peaks were robust across fMRI protocols (∆TTP: −0.15 vs. −0.053, p = 0.239; correlation at aligned peaks: 0.813 vs. 0.812, p = 0.985) and demonstrated good to excellent within-subject reproducibility (∆TTP: intraclass correlation coefficient = 0.36; correlation at aligned peaks: intraclass correlation coefficient = 0.89). This study proposes a non-invasive technique to evaluate vascular and paravascular fluid dynamics. Our findings reveal a consistent and robust cardiac pulsation-driven coupling between cerebral hemodynamics and pCSF dynamics in both younger and older adults.
心脏搏动推动血液流经脑血管网络,以维持大脑的平衡。脑血管网络周围有独特的血管旁脑脊液(pCSF),它在清除废物方面起着至关重要的作用,其流动被怀疑是由动脉搏动驱动的。尽管其重要性不言而喻,但人类对整个心动周期中血管和血管旁液体动力学之间的关系仍然知之甚少。在这项研究中,我们开发了一种非侵入性神经成像方法来研究人脑蛛网膜下腔内血管搏动和 pCSF 动态之间的耦合关系。我们对静息态功能磁共振成像(fMRI)和动态弥散加权成像(dynDWI)进行了回溯性心脏配准,以分别表示脑血流动力学和 pCSF 运动。我们测量了 $$frac{d}{dphi }fMRI$$ 和 dynDWI 波形的峰值间隔时间(∆TTP),并通过计算峰值对齐后的波形相关性(峰值对齐时的相关性)来测量它们之间的耦合。我们比较了年轻人[平均年龄:27.9 (3.3)岁,n = 9]和老年人[平均年龄:70.5 (6.6)岁,n = 20]的 ∆TTP 和峰值对齐时的相关性,并评估了它们在受试者内部和不同成像方案中的可重复性。血流动力学变化始终先于 pCSF 运动。与老年人相比,年轻人的 ∆TTP 明显较短(-0.015 对 -0.069,P < 0.05)。对齐峰值的相关性很高,年轻人和老年人之间没有差异(0.833 vs. 0.776,p = 0.153)。在不同的 fMRI 方案中,对齐峰的 ∆TTP 和相关性都很稳定(∆TTP:-0.15 vs. -0.053,p = 0.239;对齐峰相关性:0.813 vs. 0.812,p = 0.985),并表现出良好至卓越的受试者内重现性(∆TTP:类内相关系数 = 0.36;对齐峰相关性:类内相关系数 = 0.89)。这项研究提出了一种评估血管和血管旁流体动力学的无创技术。我们的研究结果表明,在年轻人和老年人中,脑血流动力学和 pCSF 动力学之间存在一致且强大的心脏搏动驱动耦合。
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引用次数: 0
Response to Commentary on “Structural characterization of SLYM – a 4th meningeal membrane” by Julie Siegenthaler and Christer Betsholtz 对 Julie Siegenthaler 和 Christer Betsholtz 就 "SLYM--第四脑膜的结构特征 "发表的评论的回应
IF 7.3 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-09 DOI: 10.1186/s12987-024-00567-z
Virginia Plá, Styliani Bitsika, Michael J. Giannetto, Antonio Ladrón-de-Guevara, Daniel Gahn-Martinez, Yuki Mori, Maiken Nedergaard, Kjeld Møllgård
Histological studies have for decades documented that each of the classical meningeal membranes contains multiple fibroblast layers with distinct cellular morphology. Particularly, the sublayers of the arachnoid membranes have received attention due to their anatomical complexity. Early studies found that tracers injected into the cerebrospinal fluid (CSF) do not distribute freely but are restricted by the innermost sublayer of the arachnoid membrane. The existence of restrictions on CSF movement and the subdivision of the subarachnoid space into several distinct compartments have recently been confirmed by in vivo 2-photon studies of rodents, as well as macroscopic imaging of pigs and magnetic resonance imaging of human brain. Based on in vivo imaging and immunophenotyping characterization, we identified the structural basis for this compartmentalization of the subarachnoid space, which we term ‘Subarachnoid lymphatic-like membrane’, SLYM. The SLYM layer engages the subarachnoid vasculature as it approaches the brain parenchyma, demarcating a roof over pial perivascular spaces. Functionally, the separation of pial periarterial and perivenous spaces in the larger subarachnoid space is critical for the maintenance of unidirectional glymphatic clearance. In light of its close apposition to the pial surface and to the brain perivascular fluid exit points, the SLYM also provides a primary locus for immune surveillance of the brain. Yet, the introduction of SLYM, in terms of its anatomic distinction and hence functional specialization, has met resistance. Its critics assert that SLYM has been described in the literature by other terms, including the inner arachnoid membrane, the interlaminate membrane, the outer pial layer, the intermediate lamella, the pial membrane, the reticular layer of the arachnoid membrane or, more recently, BFB2-3. We argue that our conception of SLYM as an anatomically and functionally distinct construct is both necessary and warranted since its functional roles are wholly distinct from those of the overlying arachnoid barrier layer. Our terminology also lends clarity to a complex anatomy that has hitherto been ill-described. In that regard, we also note the lack of specificity of DPP4, which has recently been introduced as a ‘selected defining marker’ of the arachnoid barrier layer. We note that DPP4 labels fibroblasts in all meningeal membranes as well as in the trabecula arachnoides and the vascular adventitial layers, thus obviating its utility in meningeal characterization. Instead, we report a set of glymphatic-associated proteins that serve to accurately specify SLYM and distinguish it from its adjacent yet functionally distinct membranes.
数十年来的组织学研究表明,每种典型的脑膜都包含多个具有不同细胞形态的成纤维细胞层。特别是蛛网膜下层,由于其解剖结构的复杂性而受到关注。早期研究发现,注入脑脊液(CSF)的示踪剂不会自由分布,而是受到蛛网膜最内层亚层的限制。最近,啮齿类动物的活体双光子研究、猪的宏观成像和人脑的磁共振成像都证实了 CSF 运动受限和蛛网膜下腔细分为多个不同区室的事实。根据体内成像和免疫分型特征,我们确定了蛛网膜下腔这种分区的结构基础,我们称之为 "蛛网膜下腔淋巴样膜"(SLYM)。蛛网膜下腔淋巴样膜层在接近脑实质时与蛛网膜下腔血管相接,为皮质血管周围空间划分了一个屋顶。从功能上讲,在较大的蛛网膜下腔中分离出桡动脉周围空间和静脉周围空间对于维持单向的血糖清除至关重要。由于蛛网膜下腔与髓腔表面和脑血管周围液体出口点紧密相连,因此蛛网膜下腔也是对大脑进行免疫监视的主要场所。然而,SLYM 在解剖学上的区别以及因此而产生的功能特异性,使它的引入遇到了阻力。批评者认为,文献中对 SLYM 的描述还有其他术语,包括蛛网膜内层、层间膜、髓外层、中间层、髓膜、蛛网膜网状层或最近的 BFB2-3。我们认为,由于 SLYM 的功能作用与上覆蛛网膜屏障层的功能作用完全不同,因此我们将 SLYM 视为一个在解剖学和功能上截然不同的结构是必要的,也是合理的。我们的术语还使迄今为止描述不清的复杂解剖结构更加清晰。在这方面,我们还注意到 DPP4 缺乏特异性,最近有人将其作为蛛网膜屏障层的 "选定定义标记"。我们注意到,DPP4 可标记所有脑膜以及蛛网膜小梁和血管临近层中的成纤维细胞,因此它在脑膜特征描述中并不实用。相反,我们报告了一组与淋巴相关的蛋白,这些蛋白有助于准确确定 SLYM,并将其与邻近但功能不同的膜区分开来。
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引用次数: 0
Commentary on “Structural characterization of SLYM – a 4th meningeal membrane” 关于 "第 4 层脑膜 SLYM 的结构特征 "的评论
IF 7.3 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-09-09 DOI: 10.1186/s12987-024-00568-y
Julie Siegenthaler, Christer Betsholtz
For centuries, the meninges have been described as three membranes: the inner pia, middle arachnoid and outer dura. It was therefore sensational when in early 2023 Science magazine published a report of a previously unrecognized — 4th — meningeal membrane located between the pia and arachnoid. Multiple features were claimed for this new membrane: a single cell layer marked by the transcription factor Prox1 that formed a barrier to low molecular weight substances and separated the subarachnoid space (SAS) into two fluid-filled compartments, not one as previously described. These features were further claimed to facilitate unidirectional glymphatic cerebrospinal fluid transport. These claims were immediately questioned by several researchers as misinterpretations of the authors’ own data. The critics argued that (i) the 4th meningeal membrane as claimed did not exist as a separate structure but was part of the arachnoid, (ii) the “outer SAS” compartment was likely an artifactual subdural space created by the experimental procedures, and (iii) the 4th membrane barrier property was confused with the arachnoid barrier. Subsequent publications in late 2023 indeed showed that Prox1 + cells are embedded within the arachnoid and located immediately inside of and firmly attached to the arachnoid barrier cells by adherens junctions and gap junctions. In a follow-up study, published in this journal, the lead authors of the Science paper Kjeld Møllgård and Maiken Nedergaard reported additional observations they claim support the existence of a 4th meningeal membrane and the compartmentalization of the SAS into two non-communicating spaces. Their minor modification to the original paper was the 4th meningeal membrane was better observable at the ventral side of the brain than at the dorsal side where it was originally reported. The authors also claimed support for the existence of a 4th meningeal membrane in classical literature. Here, we outline multiple concerns over the new data and interpretation and argue against the claim there is prior support in the literature for a 4th meningeal membrane.
几个世纪以来,脑膜一直被描述为三层膜:内层蝶鞍膜、中层蛛网膜和外层硬脑膜。因此,2023 年初,《科学》杂志发表了一篇关于位于椎孔和蛛网膜之间、以前从未被认识到的第四层脑膜的报道,引起了轰动。这层新膜被认为具有多种特征:以转录因子 Prox1 为标志的单细胞层对低分子量物质形成屏障,并将蛛网膜下腔(SAS)分隔成两个充满液体的区域,而不是之前描述的一个区域。这些特征还被认为有利于单向脑脊液运输。这些说法立即受到一些研究人员的质疑,认为是对作者自己数据的误读。批评者认为:(i) 作者声称的第 4 层脑膜并非作为一个独立的结构存在,而是蛛网膜的一部分;(ii) "外 SAS "隔室很可能是实验过程中人为制造的硬膜下空间;(iii) 第 4 层膜屏障特性与蛛网膜屏障相混淆。随后在 2023 年底发表的论文确实表明,Prox1 + 细胞嵌入蛛网膜内,紧靠蛛网膜屏障细胞内部,并通过粘连接头和间隙连接牢固地附着在蛛网膜屏障细胞上。在本刊发表的后续研究中,《科学》论文的主要作者谢尔德-莫尔高德(Kjeld Møllgård)和迈肯-内德加德(Maiken Nedergaard)报告了他们的其他观察结果,他们声称这些观察结果支持第4脑膜的存在,并支持将SAS分成两个非交流空间。他们对原论文稍作修改,即第 4 层脑膜在大脑腹侧的观察结果比在背侧的观察结果要好,而在背侧的观察结果则没有原报告的那么好。作者还声称经典文献支持第四脑膜的存在。在此,我们概述了对新数据和解释的多方面担忧,并反驳了之前文献中存在第四脑膜的说法。
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引用次数: 0
CSF dynamics throughout the ventricular system using 4D flow MRI: associations to arterial pulsatility, ventricular volumes, and age. 使用四维血流 MRI 观察整个心室系统的 CSF 动态:与动脉搏动、心室容积和年龄的关系。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-30 DOI: 10.1186/s12987-024-00570-4
Tomas Vikner, Kevin M Johnson, Robert V Cadman, Tobey J Betthauser, Rachael E Wilson, Nathaniel Chin, Laura B Eisenmenger, Sterling C Johnson, Leonardo A Rivera-Rivera

Background: Cerebrospinal fluid (CSF) dynamics are increasingly studied in aging and neurological disorders. Models of CSF-mediated waste clearance suggest that altered CSF dynamics could play a role in the accumulation of toxic waste in the CNS, with implications for Alzheimer's disease and other proteinopathies. Therefore, approaches that enable quantitative and volumetric assessment of CSF flow velocities could be of value. In this study we demonstrate the feasibility of 4D flow MRI for simultaneous assessment of CSF dynamics throughout the ventricular system, and evaluate associations to arterial pulsatility, ventricular volumes, and age.

Methods: In a cognitively unimpaired cohort (N = 43; age 41-83 years), cardiac-resolved 4D flow MRI CSF velocities were obtained in the lateral ventricles (LV), foramens of Monro, third and fourth ventricles (V3 and V4), the cerebral aqueduct (CA) and the spinal canal (SC), using a velocity encoding (venc) of 5 cm/s. Cerebral blood flow pulsatility was also assessed with 4D flow (venc = 80 cm/s), and CSF volumes were obtained from T1- and T2-weighted MRI. Multiple linear regression was used to assess effects of age, ventricular volumes, and arterial pulsatility on CSF velocities.

Results: Cardiac-driven CSF dynamics were observed in all CSF spaces, with region-averaged velocity range and root-mean-square (RMS) velocity encompassing from very low in the LVs (RMS 0.25 ± 0.08; range 0.85 ± 0.28 mm/s) to relatively high in the CA (RMS 6.29 ± 2.87; range 18.6 ± 15.2 mm/s). In the regression models, CSF velocity was significantly related to age in 5/6 regions, to CSF space volume in 2/3 regions, and to arterial pulsatility in 3/6 regions. Group-averaged waveforms indicated distinct CSF flow propagation delays throughout CSF spaces, particularly between the SC and LVs.

Conclusions: Our findings show that 4D flow MRI enables assessment of CSF dynamics throughout the ventricular system, and captures independent effects of age, CSF space morphology, and arterial pulsatility on CSF motion.

背景:脑脊液(CSF)动力学在衰老和神经系统疾病中的研究日益增多。脑脊液介导的废物清除模型表明,脑脊液动力学的改变可能在中枢神经系统有毒废物的积累中发挥作用,并对阿尔茨海默病和其他蛋白质病产生影响。因此,对 CSF 流速进行定量和容积评估的方法很有价值。在这项研究中,我们证明了四维血流磁共振成像同时评估整个脑室系统中 CSF 动态的可行性,并评估了与动脉搏动性、脑室容积和年龄的关联:方法:在一组认知功能未受损的人群(N = 43;年龄 41-83 岁)中,使用 5 厘米/秒的速度编码(venc),在侧脑室(LV)、门罗穹窿、第三和第四脑室(V3 和 V4)、脑导水管(CA)和椎管(SC)获得了心脏分辨 4D 血流 MRI CSF 速度。脑血流搏动性也通过 4D 流量(venc = 80 厘米/秒)进行评估,脑脊液体积则通过 T1 和 T2 加权核磁共振成像获得。采用多元线性回归评估年龄、心室容积和动脉搏动对 CSF 速度的影响:结果:在所有CSF间隙都观察到了心脏驱动的CSF动力学,区域平均速度范围和均方根速度(RMS)从左心室的极低(RMS 0.25 ± 0.08;范围 0.85 ± 0.28 mm/s)到CA的相对较高(RMS 6.29 ± 2.87;范围 18.6 ± 15.2 mm/s)。在回归模型中,5/6 个区域的 CSF 速度与年龄显著相关,2/3 个区域的 CSF 空间体积与年龄显著相关,3/6 个区域的 CSF 速度与动脉搏动率显著相关。组平均波形显示整个CSF间隙的CSF血流传播延迟明显,尤其是在SC和左心室之间:我们的研究结果表明,四维血流 MRI 能够评估整个心室系统的 CSF 动态,并捕捉年龄、CSF 空间形态和动脉搏动对 CSF 运动的独立影响。
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引用次数: 0
Regulation of folate transport at the mouse arachnoid barrier. 小鼠蛛网膜屏障对叶酸转运的调节。
IF 5.9 1区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-27 DOI: 10.1186/s12987-024-00566-0
Vishal Sangha, Sara Aboulhassane, Reina Bendayan

Background: Folates are a family of B9 vitamins essential for normal growth and development in the central nervous system (CNS). Transport of folates is mediated by three major transport proteins: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate uptake occurs at the choroid plexus (CP) epithelium through coordinated actions of FRα and PCFT, or directly into brain parenchyma at the vascular blood-brain barrier (BBB), mediated by RFC. Impaired folate transport can occur due to loss of function mutations in FRα or PCFT, resulting in suboptimal CSF folate levels. Our previous reports have demonstrated RFC upregulation by nuclear respiratory factor-1 (NRF-1) once activated by the natural compound pyrroloquinoline quinone (PQQ). More recently, we have identified folate transporter localization at the arachnoid barrier (AB). The purpose of the present study was to further characterize folate transporters localization and function in AB cells, as well as their regulation by NRF-1/PGC-1α signaling and folate deficiency.

Methods: In immortalized mouse AB cells, polarized localization of RFC and PCFT was assessed by immunocytochemical analysis, with RFC and PCFT functionality examined with transport assays. The effects of PQQ treatment on changes in RFC functional expression were also investigated. Mouse AB cells grown in folate-deficient conditions were assessed for changes in gene expression of the folate transporters, and other key transporters and tight junction proteins.

Results: Immunocytochemical analysis revealed apical localization of RFC at the mouse AB epithelium, with PCFT localized on the basolateral side and within intracellular compartments. PQQ led to significant increases in RFC functional expression, mediated by activation of the NRF-1/PGC-1α signalling cascade. Folate deficiency led to significant increases in expression of RFC, MRP3, P-gp, GLUT1 and the tight junction protein claudin-5.

Conclusion: These results uncover the polarized expression of RFC and PCFT at the AB, with induction of RFC functional expression by activation of the NRF-1/PGC-1α signalling pathway and folate deficiency. These results suggest that the AB may contribute to the flow of folates into the CSF, representing an additional pathway when folate transport at the CP is impaired.

背景:叶酸是中枢神经系统(CNS)正常生长和发育所必需的 B9 族维生素。叶酸的转运由三种主要转运蛋白介导:叶酸受体α(FRα)、质子偶联叶酸转运体(PCFT)和还原叶酸载体(RFC)。大脑叶酸的吸收是通过 FRα 和 PCFT 的协调作用在脉络丛(CP)上皮发生的,或者是在 RFC 的介导下通过血管血脑屏障(BBB)直接进入脑实质的。FRα或PCFT的功能缺失突变可导致叶酸转运受损,从而导致CSF叶酸水平不达标。我们之前的报告显示,一旦被天然化合物吡咯喹啉醌(PQQ)激活,核呼吸因子-1(NRF-1)就会上调 RFC。最近,我们确定了叶酸转运体在蛛网膜屏障(AB)的定位。本研究的目的是进一步确定叶酸转运体在AB细胞中的定位和功能,以及它们受NRF-1/PGC-1α信号传导和叶酸缺乏的调控:方法:在永生化的小鼠AB细胞中,通过免疫细胞化学分析评估了RFC和PCFT的极化定位,并用转运实验检测了RFC和PCFT的功能。此外,还研究了 PQQ 处理对 RFC 功能表达变化的影响。对叶酸缺乏条件下生长的小鼠 AB 细胞进行了评估,以了解叶酸转运体、其他关键转运体和紧密连接蛋白基因表达的变化:免疫细胞化学分析显示,RFC定位于小鼠AB上皮细胞的顶端,PCFT定位于基外侧和细胞内。通过激活 NRF-1/PGC-1α 信号级联,PQQ 导致 RFC 功能表达显著增加。叶酸缺乏导致 RFC、MRP3、P-gp、GLUT1 和紧密连接蛋白 claudin-5 的表达显著增加:这些结果揭示了 RFC 和 PCFT 在 AB 处的极化表达,NRF-1/PGC-1α 信号通路的激活和叶酸缺乏会诱导 RFC 的功能表达。这些结果表明,AB可能有助于叶酸流入脑脊液,是叶酸在CP转运受损时的另一个途径。
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引用次数: 0
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Fluids and Barriers of the CNS
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