Mechanisms of TIMP2-mediated hippocampal revitalization in Alzheimer's disease

TIMP2介导的阿尔茨海默病海马再生机制

• 批准号: 10591285
• 负责人: Joseph Michael Castellano
• 金额: $ 11.27万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591285
• 关键词: Address; Administrative Supplement; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Cell physiology; Cells; Data; Development; Disease; Environment; Epidemic; Funding; Gene Expression Profiling; Hippocampus (Brain); Homeostasis; Human; Knock-in Mouse; Learning; Mediating; Memory; Molecular; Mus; Neuroglia; Neurons; Pathway interactions; Phenotype; Plasma; Process; Proteins; Regulation; Risk Factors; Source; Tissue Inhibitor of Metalloproteinases; Tissue-Specific Gene Expression; adult neurogenesis; aging brain; cell type; improved; intercellular communication; nervous system disorder; next generation; novel; novel strategies; parent grant

Project Summary/Abstract: Given that aging is the major risk factor for many neurological disorders, including devastating diseases for which there is no cure like Alzheimer’s disease, novel approaches are needed to confront the growing epidemic. Many studies have shown that factors present within the systemic environment regulate markers of brain aging in a bidirectional (young or old) fashion, which led me to search for specific protein activities that could mediate key phenotypes. One such factor we have focused on in our funded parent grant is tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown is sufficient to improve learning and memory and is a key component of very young human plasma for mediating improved hippocampal function. Moreover, several studies implicate TIMP2 in relation to risk for Alzheimer’s disease, though the mechanism underlying this relationship (e.g., amyloid-dependent vs. amyloid-independent processes) remains unclear. We demonstrate that expression of TIMP2 is critical for cellular homeostasis and function within the hippocampus, including within glia and for the process of adult neurogenesis. Differential gene expression data in mice lacking TIMP2 indicate that various cellular processes in neural cells are disrupted. We hypothesize that specific aspects of intercellular communication among cells of the hippocampal microenvironment is regulated by TIMP2 and in a manner that regulates Alzheimer’s disease pathology, a finding that may be dependent on the source of TIMP2. We will address this hypothesis in 2 aims: (1) To address the cell type-specific regulation of TIMP2 within the hippocampus via snRNAseq and the impact of the source of its expression on cellular interactions. (2) To address the cell type-specific regulation of TIMP2 within the hippocampus in the context of amyloid and associated AD pathology in APP-knockin mice via snRNAseq and the impact of the source of its expression on cellular interactions. These aims will examine regulation of the CNS cellular microenvironment by TIMP2, which may have implications for development of novel AD therapies.

项目摘要/摘要：鉴于衰老是许多神经系统疾病的主要风险因素， 包括像阿尔茨海默病这样无法治愈的毁灭性疾病，新的方法是 需要应对日益严重的流行病。许多研究表明，系统内存在的因素 环境以双向（年轻或年老）的方式调节大脑衰老的标志，这使我搜索 用于介导关键表型的特定蛋白质活性。其中一个因素，我们已经集中在我们的 资助的父母补助金是金属蛋白酶组织抑制剂2（TIMP 2），我们已经证明这足以 改善学习和记忆，且是非常年轻人血浆的关键组分，用于介导改善的 海马功能此外，一些研究表明TIMP 2与阿尔茨海默病的风险有关， 尽管这种关系背后的机制（例如，淀粉样蛋白依赖型与非淀粉样蛋白依赖型 过程仍然不清楚。我们证明TIMP 2的表达对于细胞内稳态是至关重要的， 在海马体内，包括在神经胶质内，以及在成年神经发生过程中发挥作用。微分 缺乏TIMP 2的小鼠的基因表达数据表明，神经细胞中的各种细胞过程是 被打乱了我们假设海马神经元细胞间通讯的特定方面， 微环境受TIMP 2调节，并以调节阿尔茨海默病病理学的方式， 这可能与TIMP 2的来源有关。我们将在两个目标中解决这个假设：（1） 通过snRNAseq解决海马内TIMP 2的细胞类型特异性调节， 其表达来源于细胞相互作用。(2)为了解决细胞类型特异性调节TIMP 2， 通过snRNAseq在APP敲入小鼠中淀粉样蛋白和相关AD病理学背景下的海马 以及其表达来源对细胞相互作用的影响。这些目标将审查对 TIMP 2对CNS细胞微环境的影响，这可能对新型AD的发展具有意义 治疗