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

确定组织硬度在阿尔茨海默氏病病理发展中的作用

基本信息

批准号：
10574966
负责人：
Noah Ray Johnson
金额：
$ 21.77万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10574966
关键词：
3-Dimensional Address Aducanumab Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Alzheimer’s disease biomarker American Amyloid Amyloid beta-Protein Attention Back Biochemical Biological Markers Biomechanics Brain Caregivers Cause of Death Cell Line Cerebrum Clinical Data Dementia Development Disease Disease Progression Environment Extracellular Matrix Family Formulation Functional disorder Future Gel Healthcare Systems Hippocampus Human Immunotherapy Impaired cognition Impairment Individual Investigation Link Magnetic Resonance Elastography Mechanics Medical Modeling Molecular Neocortex Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Normal Range Organoids Pathogenesis Pathologic Pathway interactions Patients Persons Polyethylene Glycols Process Property Proteins Proteomics Research Role Senile Plaques Structure Symptoms Testing Therapeutic Tissues abeta accumulation age related aging brain astrogliosis brain tissue cognitive change disease phenotype experimental study extracellular human disease human model in vivo in vivo Model induced pluripotent stem cell mechanical properties neocortical neurofibrillary tangle formation neurogenesis neuron loss neuropathology novel photolysis progressive neurodegeneration stem cell model targeted treatment tau aggregation tau-1 therapeutic target therapeutically effective three-dimensional modeling tool viscoelasticity

项目摘要

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.

项目总结