随着社会与经济发展，我国正在逐渐进入人口老龄化阶段，与老龄化相对应的神经退行性疾病日益受到重视。在神经退行性疾病领域中，三大蛋白——Tau 蛋白、α-突触核蛋白、β 淀粉样蛋白，始终是研究的焦点。由于不同病理蛋白聚集体形成的分子机制及其传播的相关调控机制涉及多种因素，目前并没有研发出能够逆转病理进程或者治愈疾病的药物。因此，建立能够真实再现人类病理表型的临床前动物模型，对理解如阿尔兹海默病（AD）、帕金森病（PD）和其他疾病病理进展大有裨益，可加速和推进神经退行性疾病药物研发进程。
Aneuro是ACROBiosystems百普赛斯专注于神经领域的品牌，开发了一系列用于神经退行性疾病研究的预制前体纤维（PFFs），Tau-441 K18 PFFs、Tau-441/2N4R PFFs、Alpha-Synuclein PFFs等产品，助力打造神经退行性疾病模型。基于稳定的、可量化的表征以及可重复的方案的验证，PFFs在疾病模型中的结构特征和活性机制将更加明确，从而在大规模药物筛选和测试中得以应用。
★ 由高质量单体诱导：单体纯度及均一性经MALS验证≥90%，更利于PFFs的形成和保证诱导活性；
★ 单体内毒素≤1.0 EU/μg，适合各类细胞和动物实验；
★ PFF的聚集形态和招募活性经电镜、ThT及细胞水平实验全面验证，分享Protocol；
★ 货期及批间更稳定，质控更严格，性价比更高；
★ 提供更个性化的产品与服务，多种荧光标记方案可供定制选择，满足体内、体外实验不同需求。
AD的特征是存在由异常磷酸化和聚集的Tau蛋白组成的神经原纤维缠结。体外和体内研究表明，异常的Tau可以通过“朊病毒样”机制募集种子形成新的聚集体，促进病理学种子在大脑中传播。而AD研究进程的停滞，很大部分原因归结于动物AD模型不能模拟AD病人的真实情况，即缺乏一种能反应AD疾病进展和AD药物功效的动物模型。这使得很多候选药物在临床前的动物实验模型中有效，然而在人体给药时却发挥不出药效。
正常及AD患者脑部结构示意图
对于体外模型，理想的情况是能够重演AD病理过程的三大点：Aβ的累积，磷酸化Tau的聚集和神经炎性，即重演AD患者大脑中多级细胞间的相互作用。疾病模型打造极大地促进了对AD发病机制的理解。预制前体纤维（Pre-formed Fibrils，PFFs），即在体外预先制备，能够持续招募可溶性病理蛋白形成聚集体的纤维样蛋白。该系统将有助于开发更精确的人类大脑模型，用于神经胶质相互作用和药物发现的基本机制研究。这项研究还提高了人们对AD中细胞死亡的理解，并推动人类攻克AD进程。
● 高纯度经SDS-PAGE验证
Transmission electron microscopy (TEM) of Tau-441 preformed fibrils (Cat. No. TAU-H5115). Fibril structure is visible on negative stain TEM images of TAU-H5115 (Routinely tested).
Transmission electron microscopy (TEM) of Human Tau-441 K18 Pre-formed Fibrils Protein (Cat. No. TAU-H5146), His Tag (Routinely tested).
Transmission electron microscopy (TEM) of Tau-441 preformed fibrils (Cat. No. TAU-H5115). Fibril structure is visible on negative stain TEM images of TAU-H5115 (Routinely tested).
Transmission electron microscopy (TEM) of Human Tau-441 K18 Pre-formed Fibrils Protein (Cat. No. TAU-H5146), His Tag (Routinely tested).
HEK293/Human Tau (GFP) Stable Cell Line (Cat. No. CHEK-ATP087) were transduced with Human Tau-441 Pre-formed Fibrils, Tag Free (Cat. No. TAU-H5115) and Human Tau-441, Tag Free (Cat. No. TAU-H5117) respectively. The fluorescence of GFP-Tau (Green) and DAPI (Blue) were detected by confocal microscope.
HEK293/Human Tau (GFP) Stable Cell Line (Cat. No. CHEK-ATP087) were transduced with Human Tau-441 K18 Pre-formed Fibrils Protein, His Tag (Cat. No. TAU-H5146) and Human Tau-441 K18 Protein, His Tag respectively. The fluorescence of GFP-Tau (Green) was detected by confocal microscope.
Thioflavin T emission curves show increased fluorescence (correlated to tau aggregation) over time when tau wild-type monomers (Cat. No. TAU-H5117) are combined with tau wild-type Pre-formed Fibrils (Cat. No. TAU-H5115) (QC tested).
Thioflavin T emission curves show increased fluorescence (correlated to tau aggregation) over time when tau K18 monomers are combined with Human Tau-441 K18 Pre-formed Fibrils Protein, His Tag (Cat. No.TAU-H5146) (QC tested).
Alpha-Synuclein PFFs助力PD模型打造
PD是一种多发于老年人的进行性神经退行性疾病。现阶段，PD的发病机制和各作用靶点之间的联系仍是研究热点，在基础研究中模型的制备对PD的研究具有举足轻重的作用，或可为疾病进展、细胞机制等提供新见解。PD的典型神经病理标志是残存的神经元胞质内出现一种嗜酸性的路易小体。大量证据显示，Alpha-Synuclein的聚集和路易小体的形成与多巴胺神经元的死亡有着密切的联系。相比于使用神经毒素杀伤多巴胺神经元的帕金森模型，基于Alpha-Synuclein的帕金森病模型由于在时程上能够较好地模拟帕金森病发生、发展的全过程，更易发现和识别新的治疗靶点。
正常及PD患者脑部结构示意图
虽然神经退行性疾病中聚集的蛋白质可能不同，但疾病的进展和临床指征是相似的。Alpha-Synuclein作为构建神经元内路易小体的主要成分，或是构建的PD模型的主力因素。
● 高纯度经SDS-PAGE验证
Alpha-Synuclein monomer (Cat. No. ALN-H51H4) on SDS-PAGE under reducing (R) condition. The gel was stained overnight with Coomassie Blue. The purity of the protein is greater than 90%.
● PFFs的聚集形态经电镜测试验证
Transmission electron microscopy (TEM) of alpha-synuclein preformed fibrils (Cat. No. ALN-H51H4). Fibril structure is visible on negative stain TEM images of ALN-H51H4 (Routinely tested).
HEK293/Human Alpha-Synuclein (GFP) Stable Cell Line (Cat. No.CHEK-ATP085) were transduced with Human Alpha-Synuclein Pre-formed Fibrils, His Tag (Cat. No.ALN-H51H4) and Human Alpha-Synuclein, His Tag (Cat. No. ALN-H52H8) respectively. The fluorescence of GFP-Alpha-Synuclein (Green) and DAPI (Blue) were detected by confocal microscope.
●PFFs的招募活性经ThT荧光检测验证
参考文献
1. de Fisenne M A, Yilmaz Z, De Decker R, et al. Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in male mouse models[J]. Neurobiology of disease, 2022, 174: 105875.
2. Houben S, De Fisenne M A, Ando K, et al. Intravenous injection of PHF-tau proteins from Alzheimer brain exacerbates neuroinflammation, amyloid beta, and tau pathologies in 5XFAD transgenic mice[J]. Frontiers in Molecular Neuroscience, 2020, 13: 106.
3. Raza C, Anjum R. Parkinson's disease: Mechanisms, translational models and management strategies[J]. Life sciences, 2019, 226: 77-90.
4. 礼来Lilly公众号.
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