Validating pig models for Alzheimer's disease

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Project Summary/Abstract The broad goal of this proposal is to characterize and establish pig models of Alzheimer’s disease (AD). The specific purpose is to collect novel validation data in three pig AD models including APP, PSEN1, and 5xFAD pigs lacking their endogenous APP and PSEN1. Using our expertise, the pig models will be validated to reflect cellular, molecular, and behavior aspect of the disease. AD is the leading cause of dementia and affects estimated 6.2 million people in the U.S. population, yet there remains need to develop effective treatments. Rodent models of AD have provided critical information regarding the underlying pathophysiology of this disorder. However, these models cannot capture many aspects of the human physiology, and clinical drug doses cannot be examined in smaller animals. Large animal models of AD are thus needed to facilitate our understanding of this disorder and accelerate drug discovery efforts. Pigs are readily available and are considered to be an excellent biomedical model due to numerous similarities to humans, including cardiovascular, pulmonary, immune, endocrine and metabolic systems. Additionally, in comparison to rodent models, pigs are larger, have longer lifespans and a more similar brain structure compared to humans. Importantly, pigs can perform complicated cognitive tasks making them an ideal large animal model of AD, which is defined by a substantial decline in memory capabilities. Currently, there are no large animal models that accurately reflect the symptoms of Alzheimer’s disease in the U.S. To address this significant gap in the field, we will validate the first pig models of AD available in the U.S. Diversifying animal models representing human AD will be invaluable for developing therapeutics to improve the longevity and quality of life in AD. To achieve this goal, we have assembled an interdisciplinary research team including members of the National Swine Resource and Research Center (NSRRC) at the University of Missouri and the Porcine Neuroscience Facility (PNF) at Florida International University that has all the necessary expertise to develop and characterize these pig AD models. In Aim 1 we will characterize the genome and biological processes of our APP, PSEN1 and 5xFAD pig AD models to help establish them as a novel resource to biomedical community. In Aim 2 we will further validate the AD pig models for their use in AD research by performing brain region-specific histological evaluations and neurocognitive assessments. Thus, we expect to confirm phenocopies of AD in these pig models at molecular, biochemical, and cognitive levels. Collectively, this proposal will result in collection of critical data that is needed to assess the validity of these new pig models for AD, which can serve as a novel resource to the biomedical community and help advance our understanding and potential treatments of this major neurodegenerative disorder.