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

描述(申请人提供)：阿尔茨海默病(AD)的神经病理学定义是由淀粉样蛋白(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蛋白的积聚和过度磷酸化被认为是导致全面发展的AD神经病理的关键事件。在这里，我们建议使用一套独特的小分子药物(伽马分泌酶调节剂和CRFR1拮抗剂)来进一步探索新的AD治疗方法。这一应用将集中于针对AD转基因小鼠的A？和tau相关病理的药物的疗效。我们的主要假设是，旨在干扰A？42和过度磷酸化tau的产生的联合疗法将是治疗前驱症状或早期AD的有效方法。

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.