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

项目摘要 阿尔茨海默病(AD)是最常见的神经退行性疾病。然而，尽管取得了进展， 最近几年的研究发现，大多数AD患者的病因仍不清楚。这表明，新的 研究AD需要工具和新的视角。人们越来越认识到，机械信号来自于 细胞微环境(如基质硬度)在调节各种细胞行为方面起着重要作用，包括 神经和其他干细胞的迁移、扩散和分化等。最近的发现表明， 大脑的僵硬(或弹性模数)在阿尔茨海默病谱系中的变化，它与 疾病的严重性。然而，脑僵硬如何影响阿尔茨海默病的细胞和分子机制 都不清楚。更重要的是，天然的细胞外基质(ECM)不是纯弹性的，而是活的 包括大脑在内的组织是粘弹性的，在不同的特征时间内表现出应力松弛- 比例。阿尔茨海默病患者脑组织的粘弹性特性尚不清楚。这个项目的首要目标是 了解大脑的机械特性，特别是粘弹性特性及其之间的联系 与阿尔茨海默病在细胞和分子水平上的关系。我们最近开发了一种生物材料 可以概括不同类型组织的粘弹性行为的系统。使用生物材料作为 工具，我们发现基质应力松弛，除了刚性，是一个重要的力学因素。 调节细胞与细胞外基质的相互作用，指导细胞的活动，如扩散、增殖、免疫 调节、干细胞分化和组织再生。小胶质细胞维持大脑内环境平衡 调节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，小胶质细胞在阿尔茨海默病中也发挥着重要作用 病理学。这个项目背后的假设是，健康的大脑和受阿尔茨海默氏症影响的大脑 疾病会有不同的弹性和粘弹性特性，改变的大脑机械行为是一种 通过影响小胶质细胞的活性参与AD的病理过程。该项目有两个具体目标：1) 正常和阿尔茨海默病患者脑组织弹性和粘弹性的研究与表征 使用老鼠模型；2)开发水凝胶，概括健康人的弹性和粘弹性特性 和AD分别影响大脑，并以水凝胶为工具研究基质僵硬和 粘弹性对3D细胞培养中小胶质细胞活性的影响。该项目使用多学科方法来 从一个从未探索过的方向调查AD。该项目的成功完成将有 对更好地了解阿尔茨海默病并开辟脑研究新方向产生重大影响 衰老和机械生物学。这些发现也有可能导致新的诊断和治疗策略 通过确定机械转导通路作为治疗阿尔茨海默病的新药物靶点来治疗未来的疾病。

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.