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: 9911993
• 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/9911993
• 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.

项目摘要摘要 最近的研究表明，体育锻炼对认知健康有益，至少在 部分，通过对海马神经发生的影响。其他调查线索表明， 体育锻炼是最佳的健康、分化和组织整合的关键 治疗性干细胞移植。目前的提案重点是评估潜在的能力 这种化合物，BCI-838，以模拟和/或增强前神经源性和前驱认知 在“仅β寡聚体”模型和MAPT模型中研究体育锻炼的效果 P301L模型。开发脑淀粉样变性和脑淀粉样变性的有效治疗方法 脑脊椎病被认为是退伍军人事务部RRD科的任务。在……里面 为了评估II组mGluR拮抗剂(BCI-838)模拟和/或 增强体育锻炼的神经原性和先兆作用，荷兰突变体 APPE693Q“Aβ寡聚体”小鼠和MAPTP301L自闭症小鼠将接受3个月的实验 治疗(I)仅自愿运动，(Ii)仅神经源性药物治疗(II组 MGluR拮抗剂，BCI-838)，或(Iii)两者。经过处理的小鼠将接受行为测试，以 评估他们的认知表现和焦虑水平。在完成行为测试后，他们的 海马体将用于神经发生的分析和转录组的RNAseq分析。 由于脑源性神经营养因子在运动刺激的神经发生中的意义，我们还将分析 每种类型的小鼠(野生型、Aβ寡聚体、牛角型)在服药或运动后做出反应 与(I)有花蕾的/有条件的NTRK2(也称为TrkB)-/-鼠标或(Iii)a FLOXED/有条件Ntrk2F616A。鼠标经过精心设计，所有TrkB信号都是敏锐的 在口服药物NMPP1后被废除。加在一起，带花边的TrkB-/-和 FLOXED Ntrk2F616A分别提供了TrkB慢性和急性缺陷的场景 发信号。FLOXED Ntrk2F616A还将确保在所有相关的 细胞。耗尽TrkB海马体的第三种选择是注射AAV-TrkB siRNA。 这些研究的结果可能为治疗神经退行性疾病提供一种新的方法。 旨在通过利用体育锻炼刺激海马神经发生，mGluR 拮抗剂、TrkB调节剂或两种或两种以上的某种组合。这样一种方法 可以解决目前患有痴呆症的50多万退伍军人中一个主要的未得到满足的需求。 这一数字在未来几十年只会增加，如果不加以控制，将威胁到经济 全世界。