Determining the role of tissue stiffness in the development of Alzheimer's disease pathology

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PROJECT SUMMARY Alzheimer's disease is the most common form of dementia, and exerts an untold burden on patients, families and caregivers, and the U.S. healthcare system. Alzheimer's disease is a progressive neurodegenerative disorder caused by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in the brain, the two neuropathological hallmarks of Alzheimer's disease. Much effort has been devoted to understanding the molecular mechanisms of amyloid and NFT accumulation, and the majority of therapeutic approaches thus far have targeted these pathways. However, the field has yet to produce an effective therapeutic for Alzheimer's disease that can convincingly slow, halt or reverse this devastating illness. Recently, the biomechanical properties of brain tissues have emerged as a potentially useful biomarker, as the brains of Alzheimer's disease patients have been consistently shown to have decreased mechanical stiffness relative to those of healthy subjects. These biomechanical changes are likely due to a combination of the effects of neurodegeneration and changes to the composition and structure of brain extracellular matrix (BECM). Importantly, neurodegeneration correlates well with clinical symptoms of Alzheimer's disease, whereas changes in the BECM occur years to decades prior to cognitive decline, suggesting that they are intricately connected with disease pathogenesis. Herein, we propose to systematically evaluate the contribution of BECM biomechanical properties to the development of Alzheimer's disease neuropathology. Unfortunately, in vivo models offer very limited capacity to regulate the mechanical stiffness of brain tissue. Therefore, we have developed novel three-dimensional (3D) decellularized BECM-based models with tunable mechanical properties, and have demonstrated that we can vary the model stiffness within the range of normal and Alzheimer's disease human brain tissue. We have also developed 3D cerebral organoid (CO) models using human induced pluripotent stem cells (hiPSCs) derived from Alzheimer's disease patients or from healthy controls (HC). We found that, relative to HC COs, Alzheimer's disease COs have decreased mechanical stiffness and develop progressive amyloid plaques and NFTs and neurodegeneration. Herein, we propose to embed COs within 3D BECM models, enabling high-throughput experimentation of the relationship between tissue biomechanics and Alzheimer's disease pathophysiology. We will test the hypothesis that the Alzheimer's disease neuropathology within the CO is intricately linked with BECM mechanical properties, and that increasing the BECM mechanical stiffness will reduced Alzheimer's disease phenotypes. These experiments will establish 3D BECM-CO as a new tool for investigation at the intersection of tissue biomechanics and disease pathobiology, and aims to identify a new mechanistic pathway contributing to Alzheimer's disease that has the potential to be modified therapeutically to alter disease trajectory.