National Swine Resource and Research Center 1

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Project Summary/Abstract The overall goal of this proposal is to examine the unique role of APP and PSEN1 for progression of the Alzheimer's disease (AD) by using novel pig models. Alzheimer's disease is the leading cause of dementia and affects 10% of the U.S. population. Unfortunately, currently no treatment option that can reverse trajectory of the disease exists. Mouse models of AD have been critical to identify the underlying pathophysiology of this disorder. However, these models often do not recapitulate all symptoms of the human condition, indicating that additional animal models of AD are 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 anatomical and physiological similarities to humans. In addition, in comparison to rodent models, pigs have a more similar brain structure to humans and can perform more complicated cognitive tasks that better model human behavior. Recent controversial reports on the importance of amyloid plaques for the progression of AD suggest the need to investigate potential role of APP and PSEN1 that are independent of amyloid plaques. Because specific polymorphisms of APP and PSEN1 are connected to the prevalence of early onset AD, i.e. Familial Alzheimer's disease, understanding the roles of APP and PSEN1 could elucidate pathogenesis of AD. While working on the previous NOT- AG-20-034, we have generated APP knockout pigs and PSEN1 mutant pigs carrying AD associated allele (ΔE9). Investigating the phenotype of APP-/-, PSEN1+/ΔE9, and APP-/-PSEN1+/ΔE9 pigs should reveal novel roles of APP and PSEN1 that are not linked to the amyloid deposit in brain. To the best of our knowledge, our proposed work will offer a novel large animal model to dissect pathogenesis of AD from a new perspective. We propose two aims. In Aim 1, we will investigate the phenotype of AD pig models at the cellular and biochemical level. Brain from the pigs will be collected at 6-8 months of age and signs of AD at the cellular and molecular level will be explored. In Aim 2, we will image the brain of the pig models by using MRI to follow potential atrophy caused by the genetic modifications. The imaging work will allow us to monitor signs of AD progression in these pig models and also help us optimize approaches to image the pig brain. Conventional mouse AD models do capture some AD symptoms; however, due to differences in physiology and size of brain, it is rare that findings from the models are transferred to the clinic. Diverse animal models reflecting phenotypes of human AD patient should be invaluable to design novel remedies and translate the findings into the clinic. Here, we propose to study the role of APP and PSEN1 for the progression of AD by using novel pig models. We have expertise to complete the proposed experiment within the grant timeframe and the utilization of pig models for AD can serve as a novel resource to the biomedical community and help advance our understanding and potential treatment of this major neurodegenerative disorder.