We are submitting in response to NOT-AG-18-039, ?Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease?. In our parent R01 grant ?Epigenetics of Down syndrome?, we are using mouse models to address the mechanisms of altered epigenetic patterning in Down syndrome (DS; trisomy 21), and how the epigenetic changes can affect developmental phenotypes in the brain and immune system. Here, we propose to expand to study epigenetic and biological aging and its possible role in Alzheimer?s disease (AD), using our triple-duplication (triple-Dp) complete chromosomally engineered mouse model of DS. Early-onset Alzheimer?s disease (AD) is nearly fully penetrant in people with DS, and there is some evidence that DS might be an early aging (?progeroid?) syndrome. Our long-term objective is to ask whether measuring biological and molecular markers of aging in chromosomally engineered mouse models of DS can help to answer four important questions: (i) what are the genes on chromosome 21 (Hsa21) that cause early aging of DNA methylation patterns (epigenetic aging) in DS? (ii) what are the genes on Hsa21 that cause early biological aging in DS (iii) does epigenetic aging influence biological aging? and (iv) does early biological aging contribute to the early onset of AD? In this 1-year supplement we seek to establish baseline information on aging in the complete triple-Dp mouse model of DS, which will be crucial for future work, using mouse genetics, to achieve our long-term goals. We have two aims: (1) carry out DNA methylation and transcriptome profiling in brain and T lymphocytes, at defined ages, to test the hypothesis that increased epigenetic aging in DS starts early in development and is then perpetuated throughout the adult lifespan. (2) quantitatively assess biological aging and AD-type pathology in the same model at the same ages as in Aim 1, using well standardized biomarkers of aging in the immune system, CNS, and auditory system. We will also analyze the triple-Dp mice for neuronal cell losses and learning and memory deficits at each of those ages. By comparing the data in wild-type mice and our complete DS model carrying the triplications of all Hsa21 syntenic regions, we will take the first steps toward localizing the genomic segments that account for increased epigenetic and biological aging in DS - which will allow us to test whether early biological aging synergizes with other factors, including the APP gene, in accelerating the onset of AD. These data will set the stage for identifying Hsa21 gene ortholog(s) that lead to early aging, and for dissecting the relationship between early aging and AD.
Early-onset Alzheimer?s disease (AD) is nearly fully penetrant in people with Down syndrome (DS; trisomy 21), and there is some evidence that DS might be an early aging (?progeroid?) syndrome. Our long-term objective is to ask whether measuring biological and molecular markers of aging in chromosomally engineered mouse models of DS can help to answer (i) what are the genes on chromosome 21 that cause early aging of DNA methylation patterns (epigenetic aging) in DS? (ii) what are the genes on Hsa21 that cause early biological aging in DS (iii) does epigenetic aging influence biological aging? and (iv) does early biological aging contribute to the early onset of AD? In our 1-year aims we seek to establish baseline information on epigenetic and biological aging in a triple-duplication complete mouse model of DS, which will be crucial for future work, using mouse genetics, to achieve our long -term goals.
