Alzheimer?s disease (AD) is the most common neurodegenerative disease that affects over 25 million people worldwide. In AD, hyperphosphorylated tau inclusions like neurofibrillary tangles are one of the earliest changes and can predict clinical severity. As tau inclusions increase, cognitive decline and memory loss worsen over time. Since familial and sporadic AD share the same pathology and clinical symptoms, transgenic mice that express human tau can effectively model AD. However, many existing tau mouse models do not develop both cognitive deficits and robust pathology in the cortex and hippocampus, which are the primary regions of neurodegeneration in AD. In the field, there is a compelling need to develop an effective animal model of tauopathies for mechanistic and therapeutic studies. A good model of tauopathies must meet at least four criteria: 1) develops progressive phosphorylated tau inclusions; 2) affects the primary brain regions of cortex and hippocampus like in AD patients; 3) causes cognitive deficits; and 4) is reproducible with stable germline transmission. To meet this demand, my main translational research goal is to develop a robust animal model for 1. studying disease mechanisms of tau aggregation and hyperphosphorylation and for 2. rapid screening of drugs and therapies. Given that mice have much shorter lifespans, expression of a single disease-causing mutation may not be sufficient to induce a robust disease phenotype. In the field of neurodegeneration, multiple pathogenic mutations are commonly used to accelerate disease phenotypes in transgenic mice. For example, 3XTg-AD and 5XFAD mouse models use three and five different mutations of multiple genes respectively. As a result, I chose to enhance tau neurotoxicity by combining two disease-causing mutations (P301S/S320F) in the same gene. For this research proposal, my lab and I used pronuclear integration to generate novel transgenic mice for stable germline expression of the tau mutations P301S/S320F. With this unprecedent mouse model, I will determine the role of tau hyperphosphorylation in promoting tau aggregation, cognitive deficits and brain atrophy in Specific Aims 1 and 2.
In Specific Aim 3, I will use this novel mouse model to screen phospho-tau immunotherapies. Upon completion of this study, I will fulfill my fellowship training goals of studying disease mechanisms of tau- induced neurodegeneration and developing novel immunotherapies for the treatment of AD.

Public Health Relevance

Hyperphosphorylated tau inclusions such as neurofibrillary tangles are one of the major hallmarks of Alzheimer?s disease. In this proposal, I recently generated a novel transgenic mouse model with P301S/S320F tau mutations that develops robust cortex and hippocampus pathology that progressively accumulates with age. Using this novel model, I will study mechanisms of tau phosphorylation and aggregation and develop new phosphorylation- specific immunotherapies that directly target these tau inclusions.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Yang, Austin Jyan-Yu
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University of Florida
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