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A和Tau的毒性蛋白的过度积累，因此了解A与tau功能障碍的生物学机制对于设计有效的AD治疗方法至关重要。A是由分子剪刀的两个切口产生的（分别命名为A和？分泌酶），而Tau的主要功能是稳定微管。我们发现了4种主要蛋白质（整合素，RanBP 9，Cofilin和SSH 1），它们不仅促进A产生，而且还传递Ao Tau诱导的神经毒性信号，从而促进两种病理。抑制这些蛋白质中的任何一种都可能阻止AD的进展，因此，代表了有吸引力和可行的治疗靶点。我们已经开发出抑制这些蛋白质之一（SSH 1）的化学物质，这是学术界或工业界首次发现的蛋白质，它们不仅能有效减少A的产生，还能拮抗A诱导的神经毒性和神经细胞中的Tau功能障碍。通过利用分子、生物化学、细胞生物学、电生理学和行为学工具，我们建议1）进一步表征该途径作为Tau病理学小鼠模型中A和Tau病理学之间的中间体，2）更好地理解RanBP 9-SSH 1-Cofilin途径作为原代神经元、转染细胞中A和Tau病理学之间双向神经毒性信号传导的关键节点的物理和功能作用，在试管中，在解剖的人脑中。

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.