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

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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.