Tau mislocalization assay to screen AD therapeutics using compartmentalized chips

项目概要： 神经元缠结是阿尔茨海默病（AD）的标志，在tau蛋白从神经元中解离后形成。 微管和受影响的神经元的体树突区室的错误定位。病理性tau蛋白是 然后从受影响的神经元释放并跨突触扩散，最终导致细胞死亡。 防止胞内tau蛋白在体树突隔室中的初始错误定位， 早期治疗目标，并可能导致限制AD进展的策略。Xona Microfluidic，Inc. （“Xona”）提出开发一种可靠的、可重复的和可扩展的筛选测定，以鉴定和验证 预防细胞内tau蛋白早期错误定位的治疗靶点。该项目的目标是建立 使用该检测方法为AD和AD相关疾病提供临床前筛查服务的可行性。 初步数据表明，tau蛋白的错误定位可以在Xona专有的分区模型中建模。 通过限制Aβ诱导的神经炎性介质暴露于轴突隔室， 由此产生的tau蛋白错误定位与突触囊泡释放的增加相关，这与 AD病理生理学Xona建议在这些初步数据的基础上开发这种屏幕， 在3D中培养的人诱导多能干细胞分化的神经元，其更接近地模拟人 疾病表型比小鼠模型。目标1将确定3D文化的改善程度 在我们的分区芯片中使用这些神经元，在2D培养中进行突触成熟。目标2将 使用Aβ诱导的神经炎性介质开发tau蛋白错误定位测定。此外，我们将评估 使用已建立的筛选潜力度量，该测定用于药物筛选的可靠性和适用性。 一旦可行性得到证明，Xona将专注于与潜在客户建立合作伙伴关系，并扩大其规模。 可以筛选的化合物的数量。

PROJECT SUMMARY: Neurofibrillary tangles, a hallmark of Alzheimer's disease (AD), are formed following tau dissociation from microtubules and mislocalization to the somatodendritic compartment of affected neurons. Pathological tau is then released from affected neurons and spreads trans-synaptically eventually leading to cell death. Preventing the initial mislocalization of intracellular tau within the somatodendritic compartment presents an early therapeutic target and may lead to strategies that limit the progression of AD. Xona Microfluidic, Inc. (“Xona”) proposes to develop a reliable, reproducible, and scalable screening assay to identify and validate therapeutic targets that prevent early mislocalization of intracellular tau. The goal of this project is to establish the feasibility of providing preclinical screening services using this assay for AD and AD-related diseases. Preliminary data suggests that tau mislocalization can be modeled in Xona's proprietary compartmentalized microfluidic chips by restricting exposure of Aβ-induced neuroinflammatory media to the axonal compartment. The resulting tau mislocalization correlates with an increase in synaptic vesicle release, which is consistent with AD pathophysiology. Xona proposes to develop this screen on the basis of this preliminary data and using human induced pluripotent stem cell differentiated neurons cultured in 3D, which more closely mimic human disease phenotypes than murine models. Aim 1 will determine the extent to which 3D cultures improve synapse maturation over 2D cultures using these neurons within our compartmentalized chips. Aim 2 will develop a tau mislocalization assay using Aβ-induced neuroinflammatory media. Further, we will evaluate the reliability and suitability of this assay for drug screening using an established metric of screening potential. Once feasibility is shown, Xona will focus on forming partnerships with potential customers and scaling up the number of compounds that can be screened.