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。�的积聚和tau的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的产生的联合治疗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.