Molecular Intermediates and Regulation of the Abeta-Tau Pathogenic Cascade

描述（由申请人提供）： 由于阿尔茨海默病 (AD) 大脑的主要定义特征是称为 And Tau 的有毒蛋白质过度积累，因此了解与 tau 功能障碍相关的生物学机制对于设计有效的 AD 治疗方法至关重要。 A 是由分子剪刀（称为 β 和 β 分泌酶）对其母体蛋白 APP 进行两次切割而产生的，而 Tau 的主要功能是稳定微管。我们在一条通路中发现了 4 种主要蛋白（整合素、RanBP9、Cofilin 和 SSH1），它们不仅促进 A 的产生，而且还传递 A�o Tau 诱导的神经毒性信号，从而促进这两种病理。抑制这些蛋白质中的任何一种都可能阻止 AD 的进展，因此，代表了有吸引力且可行的治疗靶点。我们开发了抑制其中一种蛋白质 (SSH1) 的化学物质，这是学术界或工业界首次表征的化学物质，它们不仅能有效减少 A 的产生，还能对抗神经细胞中引起的神经毒性和 Tau 功能障碍。通过利用分子、生化、细胞生物学、电生理学和行为工具，我们建议1）进一步表征该通路作为Tau病理小鼠模型中And Tau病理之间的中间体，2）更好地理解RanBP9-SSH1-Cofilin通路作为原代神经元、转染细胞、试管和尸检人脑中And Tau病理之间双向神经毒性信号传导关键节点的物理和功能作用。

DESCRIPTION (provided by applicant): As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of toxic proteins called A�nd Tau, understanding the biological mechanisms by which A�onnects to tau dysfunction are critical for designing effective therapeutic treatments for AD. A�s generated from two cuts made by molecular scissors (named �and ?-secretases) in its parent protein, APP, while Tau's main function is to stabilize microtubules. We found 4 major proteins (�integrin, RanBP9, Cofilin, & SSH1) in a pathway that not only promotes Aproduction but also relays the neurotoxic signals induced by A�o Tau, thereby promoting both pathologies. Inhibiting any one of these proteins could potentially stop the progression of AD, and as such, represent attractive and viable therapeutic targets. We have developed chemicals that inhibit one of these proteins (SSH1), the first ones ever characterized in academia or industry, and they show effectiveness not only in reducing A�roduction but also antagonizing A�nduced neurotoxicity and Tau dysfunction in nerve cells. By utilizing molecular, biochemical, cell biological, electrophysiological, and behavioral tools, we propose to 1) further characterize this pathway as intermediates between A�nd Tau pathologies in mouse models of Tau pathology and 2) better understand the physical and functional role of the RanBP9-SSH1-Cofilin pathway as critical nodes for bidirectional neurotoxic signaling between A�nd Tau pathologies in primary neurons, transfected cells, in the test tube, and in autopsied human brains.