Understanding Neurodegeneration Across the Scales

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With an increasing life expectancy, neurodegeneration has arguably become the most challenging malady of the century. The most common type of neurodegeneration, Alzheimer's disease, causes a devastating and progressive loss of cognition for which there is currently no treatment or cure. Protein tangles, axonal injury, and structural degradation are classic hallmarks of Alzheimer's disease. Growing evidence suggests that these features are shared by a number of other neurodegenerative disorders including traumatic brain injury, chronic traumatic encephalopathy, and Parkinsonism. Yet, the molecular mechanisms of neurodegeneration remain poorly understood. The overall goal of this research program is to establish a mechanistic, bio-chemo-mechanical model of neurodegeneration to simulate and predict normal and abnormal neurophysiology. Towards this goal, the objective of this project is to probe, model, and simulate the tau-microtubule complex to reveal the underlying failure mechanisms of individual axons. This project is truly transformative in that it will open new avenues to understand neurodegeneration from bio-chemo-mechanical principles. This project will feed into a new multidisciplinary undergraduate/graduate course at the interface between mechanics and the neurosciences. Many members of our team are individuals from underrepresented groups who actively serve as role models in various organizations where they will promote this work and recruit underrepresented individuals to join this project. To enhance scientific and technological understanding, we will continue to participate in the National Biomechanics Day, the annual International Brain Bee competition, and Stanford Brain Day.In an integrative approach that combines theory, experiment, and simulation, this project will characterize tau structure using cryo-electron microscopy, identify the molecular mechanisms by which tau modulates microtubule assembly using molecular dynamics simulation, characterize tau-microtubule function using small angle X-ray scattering, and interpret the molecular failure mechanisms of the tau-microtubule complex using kino-geometric sampling. This knowledge will enter a multiscale computational model to predict the failure mechanisms of the axon from bio-chemo-mechanical principles. This model will provide fundamental links between microtubule polymerization, tau-microtubule binding, and tau-tau cross-linking on the molecular level and stiffness, viscosity, and damage on the cellular level to quantitative failure thresholds for the tau-microtubule and tau-tau interfaces, the microtubule bundle, and the axon as a whole. This project will have broad scientific, social, and economic impact, in that it will stimulate discovery in neurodegeneration and provide enabling, biomechanics-based technologies to characterize damage thresholds, identify potential drug targets, and design inhibitors to slow down, block, or reverse neurodegenerative disorders.