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

• 批准号: 9386268
• 负责人: FRANK M LONGO
• 金额: $ 23.77万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/9386268
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' 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; neurotropin; new therapeutic target; novel; novel therapeutics; prevent; programs; prototype; psychologic; receptor; response; small molecule; synaptic function; tau Proteins

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 本申请题为“Small Molecule Neurotrophin Receptor Ligands to Treat Alzheimer's Disease”， 对NIH神经系统疾病药物发现的响应（R21; PAR-16-042）。我们将确定是否小 靶向TrkB和TrkC神经营养因子（NT）受体的分子配体将抑制基本的 AD的病理生理机制。在AD中，多种过程包括衰老、 淀粉样蛋白和病理形式的tau，以及炎症导致突触功能障碍，树突状细胞减少， 脊椎，以及突触和神经元的最终丧失。NT，包括脑源性神经营养因子 脑源性神经营养因子（BDNF）和神经营养因子-3（NT 3）是维持神经元的功能所必需的蛋白质配体。 突触BDNF和NT 3分别与TrkB和TrkC结合，以触发细胞内信号传导途径， 与AD中的退行性信号传导高度整合，因此位于对抗AD中的退行性信号传导的位置。此外，委员会认为， 破坏的NT信号传导有助于AD神经病理学和记忆缺陷的发展。我们 假设治疗性恢复或增强TrkB和/或TrkC信号传导将抵消 在AD中的神经退行性信号传导，从而抑制标志性AD病理学。我们的实验室发展得很小 结合并激活TrkB或TrkB和TrkC的分子NT受体配体。先前发表的研究， TrkB配体显示它进入大脑，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蛋白， 在AD的AβPPL/S小鼠模型中，这些 结果确立了小分子TrkB/C配体作为候选AD治疗剂。而大脑中的 配体足以产生神经保护作用时，给予全身，有利的脑水平后， 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，产生比原始配体更高的脑浓度， 类似于BDNF的神经营养作用。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配体将激活它们的预期受体并引发 以剂量依赖性方式抑制下游信号传导，并防止记忆缺陷和心理 在AD的AβPPL/S小鼠模型中，与TrkC一起靶向TrkB 是一种新的治疗AD的策略，据我们所知，我们的实验室是唯一的一个小的来源， 分子TrkB/TrkC配体能够测试同时靶向这两种NT受体的功效。 这种方法具有协同细胞内信号传导的潜力，如可以与Trk受体一起发生的，并且 对抗AD中所见的多方面病理机制。