Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common neurodegenerative disorder in the United States and is projected to affect 14 million people by 2060. Accumulation of tau pathology in AD strongly correlates to patients' cognitive decline. Current models of progressive tau pathology rely on either transgenic mice or tau fibrils isolated from the diseased human brain in wild-type mice. Attempts to induce tau pathology in wild-type mice using recombinant tau fibrils have failed. Recent studies have revealed structural and post-translational differences between recombinant and human-derived tau fibrils that may drive this difference in seeding capacity. The overarching goal of this fellowship is to use in vitro and in vivo methods to determine the conformational and environmental drivers of tau pathology seeding. Recent work produced truncated tau fibrils with various core structures, including one with a core that is structurally identical to the core region of AD PHFs. Yet, these recombinant fibrils lack post-translational modifications associated with neurofibrillary tangles. Proteomic work has identified post-translationally modified residues on the tau protein associated with pathology, and many of these disease-associated post-translational modifications can be introduced by producing tau in insect cells. The proposed research will take advantage of these recent innovations to assess the role of tau fibril structure and post-translational modifications in seeding capacity. Aim 1 of this work will use tau fibrils with varying core structures, including those identical to AD tau, and post-translational modifications to evaluate the pathological seeding capacity in a primary neuron culture model. Aim 2 of this work will utilize a quantitative pathology modeling workflow to quantify progressive pathological seeding of selected tau fibrils in wild-type mice over the course of nine months. The data collected and training acquired during this fellowship not only have the potential to shape future model systems in AD but will also shape and focus my trajectory towards becoming a leader in neurodegenerative research. Under this training period at Van Andel Research Institute, I will develop technical skills in image analysis, mouse neuroanatomy, and negative stain EM. I will also have ample opportunity to gain confidence in both oral and poster presentations. My collaborations with the cryo-electron microscopy core at VAI, a biotechnology company, and a world leader in tau fibril structure will allow me to gain expertise in running collaborative projects in addition to receiving additional guidance on structure-based questions in the field of neurodegenerative disease.
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