Mechanism of action deconvolution of the small-molecule pathological tau aggregation inhibitor Anle138b.
Mechanism of action deconvolution of the small-molecule pathological tau aggregation inhibitor Anle138b.
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DOI：
10.1186/s13195-023-01182-0
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发表时间：
2023-03-14
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阿尔茨海默病（AD）的一个关键组织病理学标志是神经元中存在聚集的微管相关蛋白tau的神经元缠结。Anle 138 b是一种小分子，此前已在小鼠中显示出减少tau聚集体和挽救AD疾病表型的功效。在这项工作中，我们采用生物信息学分析，包括途径富集和因果推理，在体外tau蛋白病模型。该模型由未接种或接种有来自人类AD患者的tau聚集体的培养的大鼠皮质神经元组成，两者都用Anle 138 b处理以产生其作用模式的假设。同时，我们使用了一系列人类靶点预测模型，根据Anle 138 b的化学结构预测其直接靶点。结合不同的方法，我们发现证据支持这一假设，即Anle 138 b的作用涉及几个过程，这些过程是AD进展的关键，包括胆固醇稳态和神经炎症。在途径水平上，我们发现与这两个过程相关的途径显著丰富，包括题为“胆固醇生物合成的超级途径”和“粒细胞粘附和渗出”的那些途径。通过因果推理，我们推断了SREBF 1/2（参与胆固醇调节）和炎症反应介质（如NFKB 1和RELA）的差异活性。值得注意的是，我们的发现也在Anle 138 b处理的非种子神经元中观察到，这意味着推断的过程与tau病理学无关，因此代表了化合物在细胞系统中的直接作用。通过基于结构的配体-靶点预测，我们预测细胞内胆固醇载体NPC 1以及NF-κB亚基是Anle 138 B的潜在靶点，模型训练集中结构相似的化合物已知靶向相同的蛋白质。这项研究为Anle 138 b的潜在作用机制产生了可行的假设，这将使未来的分子干预措施能够发展，旨在减少AD患者的tau病理学。在线版本包含补充材料，可通过10.1186/s13195-023-01182-0获得。
A key histopathological hallmark of Alzheimer’s disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes. In this work, we employed bioinformatics analysis—including pathway enrichment and causal reasoning—of an in vitro tauopathy model. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure. Combining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled “Superpathway of cholesterol biosynthesis” and “Granulocyte adhesion and diapedesis”. With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins. This study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients. The online version contains supplementary material available at 10.1186/s13195-023-01182-0.
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影响因子：
8.6
作者：
Aniceto N;Freitas AA;Bender A;Ghafourian T
通讯作者：
Ghafourian T
影响因子：
9
作者：
Brendel, Matthias;Deussing, Maximilian;Rominger, Axel
通讯作者：
Rominger, Axel
影响因子：
8.8
作者：
Calafate, Sara;Buist, Arjan;Moechars, Diederik
通讯作者：
Moechars, Diederik
影响因子：
4
作者：
Hansmannel, Franck;Sillaire, Adeline;Lambert, Jean-Charles
通讯作者：
Lambert, Jean-Charles
DOI：
10.1093/brain/aww137
发表时间：
2016-08
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Bondulich MK;Guo T;Meehan C;Manion J;Rodriguez Martin T;Mitchell JC;Hortobagyi T;Yankova N;Stygelbout V;Brion JP;Noble W;Hanger DP
通讯作者：
Hanger DP