Proneurogenic Treatment for Amyloid or Tau-Based Neurodegeneration

针对淀粉样蛋白或 Tau 神经变性的促神经源性治疗

• 批准号: 10378457
• 负责人: SAMUEL E. GANDY
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378457
• 关键词: Acute; Address; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Anxiety; Biological Assay; Brain-Derived Neurotrophic Factor; Cells; Cerebrum; Chronic; Cognitive; Dementia; Engineering; Ensure; Evaluation; Exercise; Frontotemporal Dementia; Health; Hippocampus (Brain); Human; Implant; Injections; Investigation; LoxP-flanked allele; Mission; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurotrophic Tyrosine Kinase Receptor Type 2; Oral; Pharmaceutical Preparations; Pharmacotherapy; Physical Exercise; Prodrugs; Role; Signal Transduction; Small Interfering RNA; Tauopathies; Tissues; Veterans; abeta oligomer; base; behavior test; cerebral amyloidosis; cognitive performance; cooperative study; effective therapy; learned behavior; metabotropic glutamate receptor 2; mouse model; mutant; neurogenesis; novel strategies; response; stem cell therapy; tau Proteins; transcriptome; transcriptome sequencing

Project Summary Abstract Recent studies indicate that physical exercise exerts benefits on cognitive health, at least in part, through effects on hippocampal neurogenesis. Other lines of investigation indicate that physical exercise is essential for the optimum health, differentiation, and tissue integration of therapeutic stem cell implants. The current proposal is focused on assessing the potential ability of this compound, BCI-838, to mimic and/or potentiate the proneurogenic and procognitive effects of physical exercise when studied in either the “Aβ oligomer only” model and a MAPT P301L model of tauopathy. Developing effective treatments for both cerebral amyloidosis and cerebral tauopathy is considered to be within the mission of the RRD section of VA ORD. In order to assess the potential ability of a Group II mGluR antagonist (BCI-838) to mimic and/or potentiate the proneurogenic and procognitive effects of physical exercise, Dutch mutant APPE693Q “Aβ oligomer only” mice and MAPTP301L tauopathy mice will be undergo 3 mo treatment with either (i) voluntary exercise only, (ii) proneurogenic drug treatment only (Group II mGluR antagonist, BCI-838), or (iii) both. The treated mice will undergo behavioral tests to assess their cognitive performance and anxiety levels. After finishing behavioral tests, their hippocampi will be used for an assay of neurogenesis and RNAseq assay of transcriptome. Because of the implication of BDNF in exercise-stimulated neurogenesis, we will also analyze each type of mouse (wildtype, Aβ oligomer, tauopathy) for drug or exercise response after crossing with either (i) a floxed/conditional Ntrk2(also known as trkB)-/- mouse or (iii) a floxed/conditional Ntrk2F616A. The mouse is engineered such that all trkB signaling is acutely abolished following oral treatment with the drug NMPP1. Together, the floxed trkB-/- and the floxed Ntrk2F616A provide scenarios of chronic and acute deficiencies, respectively, of trkB signaling. The floxed Ntrk2F616Awill also ensure that trkB signaling is abrogated in all relevant cells. A third option for depleting the hippocampus of trkB is the injection of AAV-trkB siRNA. The results of these studies could inform a novel approach to neurodegenerative diseases aimed at stimulating hippocampal neurogenesis, through the use of physical exercise, mGluR antagonists, trkB modulators, or some combination of two or more of these. Such an approach could address a major unmet need among the over 500,000 Veterans now living with dementia. This figure will only increase in the coming decades, and, if unchecked, threatens economies worldwide.

项目概要 摘要 最近的研究表明，体育锻炼对认知健康有好处，至少在 部分是通过对海马神经发生的影响。其他调查线表明 体育锻炼对于最佳健康、分化和组织整合至关重要 治疗性干细胞植入物。当前提案的重点是评估潜在能力 该化合物 BCI-838 可以模拟和/或增强前神经源性和促认知性 在“仅 Aβ 寡聚体”模型和 MAPT 模型中研究时体育锻炼的影响 tau蛋白病的P301L模型。开发针对脑淀粉样变性和脑淀粉样变性的有效治疗方法 脑 tau 病被认为属于 VA ORD 的 RRD 部门的职责范围。在 为了评估 II 组 mGluR 拮抗剂 (BCI-838) 模拟和/或 增强体育锻炼的促神经生成和促认知作用，荷兰突变体 APPE693Q“仅 Aβ 寡聚体”小鼠和 MAPTP301L tau 蛋白病小鼠将接受 3 个月的治疗 (i) 仅自愿锻炼，(ii) 仅促神经源药物治疗（第 II 组） mGluR 拮抗剂，BCI-838)，或 (iii) 两者。接受治疗的小鼠将接受行为测试 评估他们的认知表现和焦虑水平。完成行为测试后，他们 海马将用于神经发生测定和转录组 RNAseq 测定。 由于 BDNF 在运动刺激的神经发生中的作用，我们还将分析 每种类型的小鼠（野生型、Aβ寡聚体、tau蛋白病）在药物或运动后的反应 与 (i) floxed/条件性 Ntrk2（也称为 trkB）-/- 小鼠或 (iii) 固定/条件 Ntrk2F616A。小鼠经过精心设计，所有 trkB 信号传导都非常灵敏 用药物 NMPP1 口服治疗后被废除。一起，floxed trkB-/- 和 floxed Ntrk2F616A 分别提供了 trkB 慢性和急性缺陷的情况 发信号。 floxed Ntrk2F616A 还将确保所有相关的 trkB 信号被废除 细胞。消耗海马 trkB 的第三种选择是注射 AAV-trkB siRNA。 这些研究的结果可以为治疗神经退行性疾病提供一种新方法 旨在通过体育锻炼刺激海马神经发生，mGluR 拮抗剂、trkB 调节剂或其中两种或更多种的某种组合。这样的做法 可以解决目前患有痴呆症的超过 500,000 名退伍军人的主要未满足需求。 这个数字在未来几十年只会增加，如果不加以控制，将会威胁到经济 全世界。