Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits

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ABSTRACT Alzheimer’s disease (AD) is one of the most important challenges of our time in the field of medicine because of its severe clinical impacts on a very large patient population and the lack of effective treatments at present. In the United States, AD currently affects approximately 5.8 million people with an estimated annual cost of care of $321 billion. By 2060, the number of AD cases is predicted to rise to 14 million people with an annual cost of care exceeding one trillion dollars. For early onset AD, the most common cause is human trisomy 21 present in the cells of individuals with Down syndrome (DS). The AD-associated pathological alterations are universally present in individuals with DS by 40 years of age, and related dementia is diagnosed in this population at 56 years of age on average, with over 80% of people with DS affected by 69 years of age. To facilitate mechanistic and therapeutic studies of AD in DS (AD-DS), the principal investigator’s laboratory has engineered a substantial number of animal models of DS based on the evolutionary conservation between humans and mice at the genomic, physiological, and pathological levels, by using Cre/loxP-mediated chromosome engineering. These animal models are being studied by laboratories around the world, and one of them is triplicated for all three mouse genomic regions orthologous to human chromosome 21. In this supplement application, we propose to take the next critical step to further optimize the animal models for studies of AD-DS as well as to develop a novel experimental system for screening for molecules that can be used to target AD-DS therapeutically. We will pursue these aims by taking advantage of our recent successes, including the unique genetic reagents we have developed. We believe that attainment of our objectives will result in unprecedented new research platforms that will generate novel insights into the mechanisms underlying AD-DS, which in turn will facilitate the development of effective preventive and therapeutic interventions for AD in both those with and without DS.