更新于：2024-11-01

SEPTIN x TAU

更新于：2024-11-01

基本信息

关联

项与 SEPTIN x TAU 相关的药物

ReS19-T

靶点

SEPTIN x TAU

作用机制

SEPTIN 刺激剂 [+1]

在研机构-

原研机构

reMYND NV

在研适应症-

非在研适应症

阿尔茨海默症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 SEPTIN x TAU 相关的临床结果

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100 项与 SEPTIN x TAU 相关的转化医学

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0 项与 SEPTIN x TAU 相关的专利（医药）

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项与 SEPTIN x TAU 相关的文献（医药）

2024-05-31·Science

Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer’s disease

Article

作者: Pipeleers, Karolien ; Princen, Katrien ; De Witte, Koen ; Brouwer, Marinka ; Wera, Stefaan ; Rousseau, Frederic ; Schymkowitz, Joost ; Annaert, Wim ; Lauwers, Annick ; Cornelissen, Tom ; Prerad, Jovan ; Hughes-Asceri, Sandrine ; van Gorsel, Marit ; Louros, Nikolaos ; Yang, Xiaojuan ; De Winter, Hans ; Busschots, Yoni ; Laghmouchi, Mohamed ; Fivaz, Marc ; Pringels, Lentel ; Carmans, Sofie ; Van Dooren, Tom ; Voets, Marieke ; Farinelli, Melissa ; Van Damme, Nele ; Rodiers, Olivier ; Debroux, Eveline ; Claes, Sofie ; Cummings, Jeffrey L ; Duhamel, Hein ; Winderickx, Joris ; de Wit, Joris ; De Ridder, Liese ; Zetterberg, Henrik ; Vanwelden, Thomas ; Dumbacher, Michael ; Griffioen, Gerard ; Vansteenkiste, Seppe ; Bastiaens, Ilse ; Tavernier, Jan ; Verhelst, Vanessa ; Coupet, Kristel ; Lievens, Sam ; Cuveliers, Eva ; Dupont, Shana

Abnormal calcium signaling is a central pathological component of Alzheimer’s disease (AD). Here, we describe the identification of a class of compounds called ReS19-T, which are able to restore calcium homeostasis in cell-based models of tau pathology. Aberrant tau accumulation leads to uncontrolled activation of store-operated calcium channels (SOCCs) by remodeling septin filaments at the cell cortex. Binding of ReS19-T to septins restores filament assembly in the disease state and restrains calcium entry through SOCCs. In amyloid-β and tau-driven mouse models of disease, ReS19-T agents restored synaptic plasticity, normalized brain network activity, and attenuated the development of both amyloid-β and tau pathology. Our findings identify the septin cytoskeleton as a potential therapeutic target for the development of disease-modifying AD treatments.

2022-02-01·Neurobiology of Disease2区 · 医学

S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5

2区 · 医学

Article

作者: Miranda-Lourenço, Catarina ; Fonseca-Gomes, João ; Ferreira, Catarina B ; Hiltunen, Mikko ; Coelho, Joana E ; Soininen, Hilkka ; Leinonen, Ville ; Haapasalo, Annakaisa ; Tanqueiro, Sara R ; Leppänen, Luukas ; Lopes, Luísa V ; Pike, Ian ; Belo, Rita F ; Sebastião, Ana Maria ; Paldanius, Kaisa M A ; de Mendonça, Alexandre ; Vaz, Sandra H ; Takalo, Mari ; Diógenes, Maria José ; Marttinen, Mikael ; Mäkinen, Petra

Alzheimer's disease (AD) is the most common form of dementia, which is neuropathologically characterized by extracellular senile plaques containing amyloid-β and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Previous studies have suggested a role for septin (SEPTIN) protein family members in AD-associated cellular processes. Here, we elucidated the potential role of presynaptic SEPTIN5 protein and its post-translational modifications in the molecular pathogenesis of AD. RNA and protein levels of SEPTIN5 showed a significant decrease in human temporal cortex in relation to the increasing degree of AD-related neurofibrillary pathology. Conversely, an increase in the phosphorylation of the functionally relevant SEPTIN5 phosphorylation site S327 was observed already in the early phases of AD-related neurofibrillary pathology, but not in the cerebrospinal fluid of individuals fulfilling the criteria for mild cognitive impairment due to AD. According to the mechanistic assessments, a link between SEPTIN5 S327 phosphorylation status and the effects of SEPTIN5 on amyloid precursor protein processing and markers of autophagy was discovered in mouse primary cortical neurons transduced with lentiviral constructs encoding wild type SEPTIN5 or SEPTIN5 phosphomutants (S327A and S327D). C57BL/6 J mice intrahippocampally injected with lentiviral wild type SEPTIN5 or phosphomutant constructs did not show changes in cognitive performance after five to six weeks from the start of injections. However, SEPTIN5 S327 phosphorylation status was linked to changes in short-term synaptic plasticity ex vivo at the CA3-CA1 synapse. Collectively, these data suggest that SEPTIN5 and its S327 phosphorylation status play a pivotal role in several cellular processes relevant for AD.

2017-02-01·Journal of Neuropathology & Experimental Neurology3区 · 医学

Association of Neuropathological Markers in the Parietal Cortex With Antemortem Cognitive Function in Persons With Mild Cognitive Impairment and Alzheimer Disease

3区 · 医学

Article

作者: Freland, Laure ; Delay, Charlotte ; Bennett, David A ; François, Arnaud ; Vandal, Milène ; Tremblay, Cyntia ; Calon, Frédéric

The associations between cognitive function and neuropathological markers in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) remain only partly defined. We investigated relationships between antemortem global cognitive scores and β-amyloid (Aβ), tau, TDP-43, synaptic proteins and other key AD neuropathological markers assessed by biochemical approaches in postmortem anterior parietal cortex samples from 36 subjects (12 MCI, 12 AD and 12 not cognitively impaired) from the Religious Orders Study. Overall, the strongest negative correlation coefficients associated with global cognitive scores were obtained for insoluble phosphorylated tau (r2 = −0.484), insoluble Aβ42 (r2 = −0.389) and neurofibrillary tangle counts (r2 = −0.494) (all p < 0.001). Robust inverse associations with cognition scores were also established for TDP-43-positive cytoplasmic inclusions (r2 = −0.476), total insoluble tau (r2 = −0.385) and Aβ plaque counts (r2 = −0.426). Sarkosyl (SK)- or formic acid (FA)-extracted tau showed similar interrelations. On the other hand, synaptophysin (r2 = +0.335), pS403/404 TDP-43 (r2 = +0.265) and septin-3 (r2 = +0.257) proteins positively correlated with cognitive scores. This study suggests that tau and Aβ42 in their insoluble aggregated forms, synaptic proteins and TDP-43 are the markers in the parietal cortex that are most strongly associated with cognitive function. This further substantiates the relevance of investigating these markers to understand the pathogenesis of AD and develop therapeutic tools.

项与 SEPTIN x TAU 相关的新闻（医药）

2024-06-08

·药明康德

阿尔茨海默病潜在新疗法登《科学》！“冷门”靶点有效保护神经

▎药明康德内容团队编辑提起阿尔茨海默病（AD），我们已经不陌生，这种神经退行性疾病是痴呆症最常见的形式，在65岁以上人群中，每9人就有1人患病。从病理学上来看，阿尔茨海默病的主要特征是两种类型的蛋白质沉积——细胞外的淀粉样蛋白β（Aβ）斑块和细胞内的tau蛋白缠结——在脑中聚集。因此，靶向Aβ的治疗策略是近年AD药物开发领域的主流，2023年获得FDA批准用以帮助AD患者减缓认知能力下降的单抗疗法便是靶向Αβ。然而相比庞大的患者人群，这类治疗的临床益处还很有限。日前，权威学术期刊《科学》的最新一期上，来自比利时的一家创新生物技术公司reMYND详细介绍了他们开发的一款阿尔茨海默病新疗法。与众不同的是，这款潜在疗法靶向的是阿尔茨海默病的一个关键细胞过程：钙信号传导。研究团队开发的小分子药物以恢复钙稳态为目标，在临床前实验中显示出有效的神经保护作用，可以减轻Αβ斑块和过度磷酸化tau聚集体的形成。论文指出，钙信号传导异常是阿尔茨海默病的病理核心。Aβ斑块和tau蛋白沉积、神经突触可塑性丧失、神经元死亡的级联过程都与钙离子稳态失衡密不可分。然而鉴于钙离子在神经元信号交流以及细胞生理学中具有核心作用，非选择性地操纵神经细胞内的钙浓度很可能导致严重的不良反应。为此，这项研究首先确立了病理条件下被过度激活的钙内流通路，并建立细胞模型模拟阿尔茨海默病的毒性tau蛋白及其诱导的钙内流，以此筛选小分子药物，鉴定出可以选择性减少钙内流及其毒性同时不影响非病理性钙水平的化合物。通过这种筛选策略，研究团队发现了有潜力的先导化合物，并经过多轮结构优化，获得了一组具有共同结构骨架的化合物分子，命名为ReS19-T。这一系列化合物可与细胞骨架蛋白septins家族相互作用，尤其是结合septin 6。 ▲ReS19-T化合物（红色所示）高亲合力结合Septins家族蛋白（图片来源：参考资料[1]） Septins是一类GTP结合蛋白，正常情况下组装成细丝作为细胞骨架的一部分，但是病理性tau会破坏septins细丝的稳定，导致钙池操纵的钙通道SOCC被无限制激活，从而发生钙超载。 ReS19-T则可以像“分子胶水”一样帮助septins重新稳定，维持细丝的完整结构，防止SOCC在病理性tau的作用下被意外激活，同时还不会影响正常生理条件下SOCC的活性。 ▲ReS19-T的作用机理：通过与septins蛋白结合促进细胞骨架稳定，防止SOCC被异常激活，从而恢复钙离子稳态（图片来源：参考资料[1]）动物实验结果表明，利用ReS19-T恢复细胞的钙离子稳态，可以起到神经保护作用。研究人员给病理性tau或Aβ驱动的两种AD模型小鼠服用了ReS19-T，发现这些化合物完全恢复了小鼠海马体的长时程增强，也就是与新记忆形成有密切关系的突触可塑性形式，逆转了空间记忆方面的缺陷，使大脑神经网络的活动趋向正常。此外AD的两大标志性病理特征，即Αβ斑块和过度磷酸化tau缠结的形成，也有明显减少。对于这种治疗阿尔茨海默病的新策略，《科学》期刊的编辑给出了积极的评价，认为靶向钙离子稳态有望成为改善AD神经退行性病变的有效策略。该论文共同通讯作者、reMYND首席科学官Gerard Griffioen博士对此表示：“研究结果突显了septin调节剂的神经保护作用，强化了我们对通过恢复钙稳态来治疗阿尔茨海默病的关注。”目前研究团队正在努力推动这一发现的临床转化，据reMYND公司新闻稿透露，第一代分子的治疗窗口相对狭窄，研究团队目前正在开发优化的第二代分子。参考资料： [1] Katrien Princen et al., Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer’s disease. Science (2024) Doi: https://doi.org/10.1126/science.add6260 [2] reMYND announces publication in Science of novel drug target with potential for development into transformative treatments for Alzheimer’s disease. Retrieved May 31, 2024 from https://flanders.bio/en/news/remynd-announces-publication-in-science-of-novel-drug-target 本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

临床1期