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 最近的研究表明，体育锻炼对认知健康有益，至少在 部分是通过影响海马神经发生。其他调查线索表明， 体育锻炼对最佳健康、分化和组织整合至关重要。 治疗性干细胞移植目前的建议侧重于评估潜在的能力， 这种化合物BCI-838，以模拟和/或加强前神经和前认知 在“仅Aβ寡聚体”模型和MAPT中研究时， tau蛋白病的P301 L模型。开发有效的治疗脑淀粉样变性和 脑tau蛋白病被认为在VA ORD的RRD部分的使命范围内。 为了评估第II组mGluR拮抗剂（BCI-838）模拟和/或 增强体育锻炼的前神经和前认知效应，荷兰突变体 APPE 693 Q“仅Aβ寡聚体”小鼠和MAPTP 301 L tau蛋白病小鼠将接受3个月的治疗。 用（i）仅自愿运动，（ii）仅前神经原性药物治疗（组II 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。在完成行为测试后， 将使用Escampi进行神经发生测定和转录组的RNAseq测定。 由于BDNF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、tau蛋白病）在给药后的药物或运动反应 与（i）floxed/条件性Ntrk 2（也称为trkB）-/-小鼠或（iii） floxed/conditional Ntrk2F616A.小鼠被设计成使得所有trkB信号传导都被急性地 在用药物NMPP 1口服治疗后消除。同时，floxed trkB-/-和 floxed Ntrk 2F 616 A分别提供了trkB的慢性和急性缺乏的情况 发信号。floxed Ntrk 2F 616 A还将确保trkB信号在所有相关的 细胞耗尽海马体trkB的第三种选择是注射AAV-trkB siRNA。 这些研究的结果可以为神经退行性疾病提供新的方法 旨在刺激海马神经发生，通过使用体育锻炼， 拮抗剂、trkB调节剂或这些中的两种或更多种的某种组合。这种做法 可以解决目前患有痴呆症的50多万退伍军人中未满足的主要需求。 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 国际吧