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)大脑的主要特征是有毒蛋白质A�和Tau的过度积聚，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。�是S在其亲本蛋白质APP中用分子剪刀(命名为�和β-分泌酶)切割产生的，而Tau的主要功能是稳定微管。我们发现了4种主要的蛋白(�整合素、RanBP9、Cofilin和SSH1.)，它们不仅促进A-�的产生，而且传递A-SSH-O-Tau诱导的神经毒性信号，从而促进这两种病理过程。抑制这些蛋白中的任何一种都可能阻止AD的进展，因此，是有吸引力和可行的治疗靶点。我们已经开发出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确定的特征，它们不仅在减少A�的产生方面显示出有效性，而且还能拮抗A�引起的神经细胞毒性和牛磺酸功能障碍。通过利用分子、生化、细胞生物学、电生理学和行为学工具，我们建议1)在Tau病理的小鼠模型中进一步表征这一通路作为A�和Tau病理之间的中介；2)更好地理解RanBP9-SSH1cofilin通路作为A�和Tau病理之间双向神经毒性信号转导的关键节点在原代神经元、转基因细胞、试管和尸检的人脑中的物理和功能作用。

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.