Molecular consequences of protein regulation on amyloid plaque burden

项目总结/文摘

PROJECT SUMMARY/ABSTRACT There are almost 6 million individuals with Alzheimer's disease (AD) in the United States, and current predictions suggest over 14 million will be affected by 2050. AD is characterized pathologically by extracellular amyloid plaques and neurofibrillary tangles. However, despite intense research focus on these features we still don't understand the mechanistic basis for cognitive decline or how the plaques and tangles are involved. Age is the largest risk factor for neurodegeneration but the molecular details that connect normal aging and neurodegenerative diseases are unclear. Caloric restriction (CR) without malnutrition delays aging and age- related diseases, including neurodegenerative diseases. A long-running trial of CR in the non-human primate rhesus monkey at the University of Wisconsin-Madison (UW) has confirmed that the benefits of CR translate to primates. Large-scale molecular profiling work to understand the CR response in these animals has revealed general downregulation of growth, immune, and inflammatory pathways and upregulation of metabolic pathways. The hepatic response to short-term CR included a novel role for RNA processing mechanisms such as alternative splicing; changes to exon usage patterns were widespread across the metabolic network recruited by CR. Rhesus monkeys develop plaques spontaneously beginning around their median lifespan of 26 years of age. Banked brain specimens from the UW Aging and CR study therefore represent a significant opportunity to study AD pathology in the context of aging in a highly translatable model. The goal of this study is to use deep sequencing proteomics to investigate the production of protein isoforms from RNA processing events and determine how they correlate with amyloid plaque burden in three brain regions. These data will then be integrated with RNAseq and other data already existing or in the process of being collected from these animals, including tau, peripheral insulin sensitivity, microglia, cognition, metabolism, and other indices, ultimately connecting RNA processing to downstream AD pathology and systemic metabolic health.