Polytherapy for AD: Combining Gamma-secretase Modulation and CRFR1 Antagonism

描述（由申请人提供）：阿尔茨海默病（AD）在神经病理学上被定义为由淀粉样蛋白（A）组成的细胞外斑块和由微管相关蛋白tau的过度磷酸化形式组成的细胞内缠结。tau蛋白的积累和过度磷酸化被认为是导致AD神经病理学全面发展的关键事件。在这里，我们建议使用一套独特的小分子药物（γ-分泌酶调节剂和CRFR 1拮抗剂），以进一步探索新的AD治疗。该申请将集中在针对AD转基因小鼠中A？和tau相关病理的药物的功效上。我们的总体假设是，旨在破坏A42和过度磷酸化tau的产生的联合治疗将是前驱或早期AD的有效治疗方法。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is defined neuropathologically by extracellular plaques composed of ¿-amyloid (A¿) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. A¿ accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose to use a unique set of small molecule drugs (gamma-secretase modulators and CRFR1 antagonists) to further explore novel AD therapeutics. This application will focus on the efficacy of drugs aimed at both A¿- and tau-related pathologies in AD transgenic mice. Our overarching hypothesis is combination therapy aimed to disrupt production of both A¿42 and hyperphosphorylated tau will be an efficacious treatment approach for prodromal or early AD.