Small molecule neurotrophin receptor ligands to treat Alzheimer's disease

项目摘要 这项名为《小分子神经营养素受体配体治疗阿尔茨海默病》的应用已在 对NIH神经系统疾病药物发现的反应(R21；PAR-16-042)。我们将确定是否很小 针对TrkB和TrkC受体的分子配体将抑制基础 阿尔茨海默病的病理生理机制。在AD中，包括老化、积累等多个过程 淀粉样蛋白和病理形态的tau，以及炎症导致突触功能障碍，树突状细胞减少 脊椎，以及最终失去突触和神经元。NTS，包括脑源性神经营养因子 脑源性神经营养因子(BDNF)和神经营养素-3(NT3)是神经元维持和功能所必需的蛋白质配体 突触。BDNF和NT3分别与TrkB和TrkC结合，触发细胞内信号通路，从而 与AD中的退化信号高度整合，因此处于与之相反的位置。此外， NT信号的紊乱参与了AD的神经病理和记忆障碍的发展。我们 假设治疗性地恢复或增强TrkB和/或TrkC信号将抵消 阿尔茨海默病中的神经退行性信号，从而抑制标志性阿尔茨海默病的病理。我们的实验室开发出了小型 结合并激活TrkB或TrkB和TrkC的NT分子受体配体。之前发表的关于 TrkB配体表明，它进入大脑，并在许多小鼠模型中具有神经保护作用 神经退行性疾病。我们对TrkB/TrkC配体的初步结果表明，它减少了tau 在AβPPL/S AD小鼠模型中，该药可改善AD的病理改变、减少树突棘丢失并改善认知。这些 结果小分子TrkB/C配体被确定为AD的候选治疗药物。而大脑的水平 当给予系统的、有利的大脑水平后，配体足以产生神经保护作用 口服给药是药物开发所必需的。为此，我们开发了这些配体的新型衍生物。 更容易进入大脑，比最初的配体产生更高的大脑浓度，并具有 神经营养作用与脑源性神经营养因子相似。因此，拟议的研究旨在确定这些新的 衍生的小分子TrkB和TrkB/TrkC配体将激活它们预期的受体并启动 以剂量依赖的方式下行信号转导，防止记忆障碍和心理障碍 βPpl/S AD小鼠模型的功能障碍及神经病理学研究与TrkC一起瞄准TrkB 是治疗AD的一种新的治疗策略，据我们所知，我们的实验室是一种小剂量 TrkB/TrkC分子配体能够测试同时靶向这两个NT受体的效果。 这种方法有可能协同细胞内信号，就像Trk受体所发生的那样，并且 对抗阿尔茨海默病的多方面病理机制。

Project Summary This application titled “Small Molecule Neurotrophin Receptor Ligands to Treat Alzheimer’s Disease” is in response to NIH Drug Discovery for Nervous System Disorders (R21; PAR-16-042). We will determine if small molecule ligands targeted to the TrkB and TrkC neurotrophin (NT) receptors will inhibit fundamental pathophysiological mechanisms underlying AD. In AD, multiple processes including aging, accumulation of amyloid and pathological forms of tau, and inflammation lead to synaptic dysfunction, decreased dendritic spines, and the eventual loss of synapses and neurons. NTs, including brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3), are protein ligands essential for the maintenance and function of neuronal synapses. BDNF and NT3 bind to TrkB and TrkC, respectively, to trigger intracellular signaling pathways that are highly integrated with, and hence situated to oppose, the degenerative signaling in AD. Furthermore, disrupted NT signaling contributes to the development of AD neuropathology and memory deficits. We hypothesize that therapeutically restoring or augmenting TrkB and/or TrkC signaling will counteract neurodegenerative signaling in AD thereby inhibiting hallmark AD pathologies. Our laboratory developed small molecule NT receptor ligands that bind to and activate TrkB or TrkB and TrkC. Previous published studies with the TrkB ligand showed that it entered the brain and was neuroprotective in numerous mouse models of neurodegenerative disorders. Our preliminary results with the TrkB/TrkC ligand showed that it reduced tau pathology, decreased dendritic spine loss, and improved cognition in the AβPPL/S mouse model of AD. These results established small molecule TrkB/C ligands as candidate AD therapeutics. While brain levels of the ligands were sufficient to produce neuroprotective effects when given systemically, favorable brain levels after oral delivery are necessary for drug development. To this end, we developed novel derivatives of these ligands that enter the brain more readily producing higher brain concentrations than the original ligands and have neurotrophic effects similar to that of BDNF. Thus, the proposed research aims to determine if these newly derived small molecule TrkB and TrkB/TrkC ligands will activate their intended receptors and initiate downstream signaling in a dose-dependent manner and prevent memory deficits and psychological disturbances as well as neuropathology in the AβPPL/S mouse model of AD. Targeting TrkB together with TrkC is a novel therapeutic strategy for AD, and, to our knowledge, our laboratory is the only source of a small molecule TrkB/TrkC ligand capable of testing the efficacy of simultaneously targeting these two NT receptors. This approach has the potential for synergistic intracellular signaling, as can occur with Trk receptors, and combatting multi-faceted pathological mechanisms seen in AD.