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

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病。尽管取得了进展， 近年来，大多数AD患者的病因仍不清楚。这表明，新 研究AD需要新的工具和视角。越来越多的人认识到， 细胞微环境（例如基质硬度）在调节各种细胞行为中起重要作用， 神经干细胞和其他干细胞的迁移、扩散和分化等。最近的研究表明， 在整个阿尔茨海默病谱系中，大脑的刚度（或弹性模量）发生变化，并且与以下因素相关 疾病严重程度。然而，脑硬度如何影响AD的细胞和分子机制 不清楚。更重要的是，天然的细胞外基质（ECM）和活的细胞外基质（ECM） 包括大脑在内的组织是粘弹性的，其在不同的特征时间内表现出应力松弛， 鳞片AD患者脑组织的粘弹性尚不清楚。该项目的总体目标是 了解大脑的机械特性，特别是粘弹性特性及其连接 在细胞和分子水平上与阿尔茨海默氏症有关。我们最近开发了一种生物材料 系统，可以概括不同类型的组织的粘弹性行为。使用生物材料作为 工具，我们发现，矩阵应力松弛，除了刚度，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动，例如扩散、增殖、免疫调节、细胞外基质的形成、细胞内基质的形成和细胞外基质的形成。 调节、干细胞分化和组织再生。小胶质细胞维持脑内稳态， 介导支持大脑的关键功能，包括控制炎症反应，吞噬细胞， 清除和组织修复越来越多的证据表明，小胶质细胞在AD中也发挥着重要作用 病理该项目的假设是，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，改变大脑的机械行为是一种 通过影响小胶质细胞的活性而促进AD病理学的因素。该项目有两个具体目标：1） 研究和表征正常和AD受累脑组织的弹性和粘弹性 使用小鼠模型; 2）开发水凝胶，其重现了健康人的弹性和粘弹性性质， 和AD分别影响大脑，并使用水凝胶作为工具来研究基质刚度和 粘弹性对3D细胞培养物中小胶质细胞活性的影响。该项目采用多学科方法， 从一个从未被探索过的方向研究AD。该项目的成功完成将使 对更好地了解阿尔茨海默病产生了重大影响，并开辟了大脑的新研究方向 老化和机械生物学。这些发现也有可能导致新的诊断策略， 在未来通过识别机械传导途径作为AD的新药物靶点来治疗该疾病。

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.