Small molecule neurotrophin receptor ligands to treat Alzheimer's disease

小分子神经营养素受体配体治疗阿尔茨海默病

基本信息

批准号：
9525783
负责人：
FRANK M LONGO
金额：
$ 19.63万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9525783
关键词：
Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Binding Bioavailable Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor California Characteristics Cognition Cognitive deficits Complex Data Degenerative Disorder Dendritic Spines Development Disease Dose Functional disorder Future Grant In Vitro Inflammation Investigation Laboratories Lead Legal patent Ligand Binding Ligands Link Long-Term Potentiation Maintenance Memory Memory impairment Mus NGFR Protein Nerve Degeneration Nerve Growth Factor Receptors Nerve Growth Factors Neurites Neurodegenerative Disorders Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Neurotrophin 3 North Carolina Oral Oral Administration Parents Pathogenesis Pathologic Pathology Pattern Penetration Phase I Clinical Trials Plasma Population Process Proteins Publishing Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Research San Francisco Signal Pathway Signal Transduction Source Synapses Techniques Testing Therapeutic United States National Institutes of Health Universities Up-Regulation Validation Vertebral column Work anxiety-like behavior base cholinergic combat design drug development drug discovery effective therapy efficacy testing improved improved functioning in vivo mouse model nervous system disorder neuronal survival neuropathology neurotrophic factor new therapeutic target novel novel therapeutics prevent programs prototype psychologic receptor response small molecule synaptic function tau Proteins

项目摘要

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.

项目摘要该应用标题为“治疗阿尔茨海默氏症的小分子神经营养蛋白受体配体”。对NIH的神经系统疾病的反应（R21； PAR-16-042）。针对TRKB和TRKC神经营养蛋白（NT）受体的分子配体将抑制基本 AD中的病理生理机制，包括衰老的多个过程 tau的淀粉样蛋白和病理形式，炎症导致突触功能障碍，减少树突状旋转以及最终的突触和神经元丧失。（BDNF）和神经营养蛋白3（NT3）是维持和功能的蛋白质配体突触。高度整合，因此与AD中的退化信号相反。 NT信号破坏有助于AD神经病理学和记忆缺陷的发展假设在治疗上恢复或增强TRKB和/或TRKC信号会抵消 AD中的神经退行性信号传导抑制了标志性AD病理。分子NT受体配体与TRKB或TRKB和TRKC结合。 TRKB配体表明它进入大脑，并且在许多小鼠模型中具有神经保护作用神经退行性疾病。病理学，树突状脊柱丧失降低，并改善了AD的Aβppl/s鼠标的认知。结果将小分子TRKB/C配体作为候选AD治疗。配体足以在全身，有利的大脑水平后产生神经保护作用口服药物药物开发是必需的。比原始配体更容易产生的浓度神经营养的作用与BDNF相似。衍生的小分子TRKB和TRKB/TRKC配体将激活预期的受体并开始以剂量依赖的方式传递下游信号，并防止记忆缺陷和心理 Aβpl/s小鼠模型AD的扰动和神经病理学。是一种新颖的AD治疗策略，而对于我们的行为是一个小的唯一来源分子TRKB/TRKC配体能够测试同时靶向两个NT受体的功效。这种方法具有协同的细胞内信号传导的潜力，TRK受体和Detors可能发生。战斗在AD中看到的多方面病理机制。