The Mechanical Properties of the Brain and Their Effect on Alzheimer's Disease

大脑的机械特性及其对阿尔茨海默病的影响

• 批准号: 10288723
• 负责人: Luo Gu
• 金额: $ 15.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288723
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid deposition; Behavior; Biochemical; Biocompatible Materials; Brain; Cells; Cerebrum; Characteristics; Diagnosis; Disease; Elasticity; Exhibits; Extracellular Matrix; Future; Goals; Homeostasis; Hydrogels; Immune; Impairment; Inflammatory; Inflammatory Response; Lead; Mechanics; Mediating; Microglia; Modulus; Molecular; Neurodegenerative Disorders; Neurons; Parietal Lobe; Pathology; Pathway interactions; Patients; Phagocytes; Play; Property; Relaxation; Research; Role; Senile Plaques; Severity of illness; Signal Transduction; Stress; System; Temporal Lobe; Testing; Time; Tissues; age related neurodegeneration; aging brain; brain tissue; cell behavior; frontal lobe; immunoregulation; in vitro Model; interdisciplinary approach; macrophage; mechanical behavior; mechanical properties; mechanotransduction; migration; mouse model; neurotoxic; new therapeutic target; relating to nervous system; stem; stem cell differentiation; stem cells; tau Proteins; three dimensional cell culture; tissue regeneration; tissue repair; tool; viscoelasticity

Project Summary Alzheimer's disease (AD) is the most common neurodegenerative disease. However, despite the progress made in recent years, the causes of AD in most patients are still not well understood. This suggests that new tools and new perspectives are needed to study AD. It is increasingly recognized that mechanical signals from cell microenvironment (e.g. matrix stiffness) play important roles in regulating various cell behaviors including migration, spreading, and differentiation of neural and other stem cells, etc. Recent findings show that the stiffness (or elastic modulus) of brain changes across the Alzheimer's disease spectrum and it correlates with disease severity. However, the cellular and molecular mechanisms of how the stiffness of brain may affect AD are unclear. More importantly, instead of being purely elastic, natural extracellular matrix (ECM) and living tissues including the brain are viscoelastic, which exhibit stress relaxation over different characteristic time- scales. The viscoelastic properties of brain with AD are unknown. The overarching goal of this project is to understand the mechanical properties, particularly the viscoelastic properties, of the brain and their connection with Alzheimer's disease at the cellular and molecular levels. We have recently developed a biomaterial system that can recapitulate the viscoelastic behavior of different types of tissues. Using the biomaterials as tools, we discovered that matrix stress relaxation, in addition to stiffness, is an important mechanical factor regulating cell–ECM interactions and directing cell activities such as spreading, proliferation, immune modulation, stem cell differentiation, and tissue regeneration. Microglia maintain cerebral homeostasis and mediate key functions to support the brain, including controlling the inflammatory response, phagocytic clearance, and tissue repair. Accumulating evidence suggests that microglia also play an important role in AD pathology. The hypothesis underlying this project is that healthy brain and the brain affected by Alzheimer's disease will have different elastic and viscoelastic properties and that altered brain mechanical behavior is a contributing factor to AD pathology by affecting the activity of microglia. This project has 2 Specific Aims: 1) Investigate and characterize the elastic and viscoelastic properties of normal and AD affected brain tissues using mouse models; 2) Develop hydrogels that recapitulate the elastic and viscoelastic properties of healthy and AD affected brain, respectively, and use the hydrogels as tools to study the effects of matrix stiffness and viscoelasticity on microglia activity in 3D cell culture. This project uses multidisciplinary approaches to investigate AD from a direction that has never been explored. Successful completion of the project will have significant impact in better understanding Alzheimer's disease and open up new research directions in brain aging and mechanobiology. The findings also have the potential to lead to new strategies for diagnosing and treating the disease in the future by identifying mechanotransduction pathways as new drug targets for AD.

项目摘要 阿尔茨海默氏病（AD）是最常见的神经退行性疾病。但是，取得进展 近年来，大多数患者的AD原因仍然不太了解。这表明新 需要工具和新的观点来研究广告。越来越认识到来自 细胞微环境（例如基质刚度）在控制各种细胞行为中起着重要作用 神经和其他干细胞的迁移，扩散和分化等。最近的发现表明 大脑在阿尔茨海默氏病谱系中的僵硬（或弹性模量）变化，它与 疾病的严重程度。但是，大脑刚度如何影响AD的细胞和分子机制 不清楚。更重要的是，而不是纯粹的弹性，天然的细胞外基质（ECM）和生活 包括大脑在内的组织是粘弹性的，在不同的特征时间内暴露了应力松弛 秤。 AD带有AD的粘弹性特性是未知的。这个项目的总体目标是 了解大脑及其连接的机械性能，尤其是粘弹性特性 在细胞和分子水平上与阿尔茨海默氏病。我们最近开发了生物材料 可以概括不同类型组织的粘弹性行为的系统。将生物材料作为 工具，我们发现矩阵应力放松除了刚度，这是一个重要的机械因素 调节细胞 - ECM相互作用和指导细胞活性，例如扩散，增殖，免疫 调节，干细胞分化和组织再生。小胶质细胞保持脑稳态和 调解关键功能以支持大脑，包括控制炎症反应，吞噬性 清除和组织修复。积累的证据表明，小胶质细胞在AD中也起着重要作用 病理。该项目的基本假设是，健康的大脑和受阿尔茨海默氏症影响的大脑 疾病将具有不同的弹性和粘弹性特性，而大脑机械行为改变是 通过影响小胶质细胞的活性来促成AD病理。该项目具有2个特定目标：1） 调查并表征正常和AD影响脑组织的弹性和粘弹性 使用鼠标模型； 2）开发水凝胶，概括了健康的弹性和粘弹性 AD分别影响了大脑，并使用水凝胶作为研究基质刚度和 3D细胞培养中小胶质细胞活性的粘弹性。该项目使用多学科的方法 从从未探索过的方向调查广告。该项目的成功完成将 更好地理解阿尔茨海默氏病并打开大脑的新研究方向的重大影响 衰老和机械生物学。这些发现还有可能导致诊断和 通过将机械转导途径鉴定为AD的新药物靶标，将来将未来治疗该疾病。