Network biology-based markers of climate-induced neurodegeneration

Project Summary – Project 2 In this project we will strive to identify the biological mechanisms by which climatic factors increase vulnerability to age-related neurodegeneration. We will leverage ongoing studies of Alzheimer’s disease in a New York City- based multi-ethnic community cohort, as well as employ laboratory models to explore biological mechanisms. We will use multi-species and multiomic approaches with network biology to identify climate-related biological vulnerabilities. One of the most obvious dynamic and unpredictable external conditions is the weather; age- associated pathologies are notably exacerbated by severe weather and temperature. Complementing Project 1, which uses national claims data to takes to examine trends in age-related diseases such as Alzheimer’s disease, this project will take a systems-level approach to delve into how climatic exposures alter biological pathways associated with age-associated neurodegeneration. We will use a combination of human prospective cohort data and well-controlled laboratory animal data to generate multiomic network models of climate-induced biological disruption. In our multi-ethnic cohort of human aging and neurodegeneration we have used an exposome-based approach to generate data from plasma samples and from brain-derived circulating extracellular vesicles (EVs). We will examine how the New York City-specific Climate Threat Index variables influence network biology and disease-related outcomes. We will also use model organisms to examine to examine the impact of a well- controlled example of climate-related disruption, namely, extreme temperatures, on biological networks. Our hypothesis is that components of the Climate Threat Index will disrupt specific biological nodes and that these disruptions will be reflected in neurodegeneration-associated outcomes. We will test this hypothesis through the following specific aims: Aim 1. To determine the effects of climate disruption on Alzheimer’s disease-related changes in network biology. The residences of cohort participants are geocoded allowing us to model complex climate factors with changes in network biology. Aim 2. To explore the use of brain-derived circulating extracellular vesicles as a source of climate-related biomarkers of neurodegeneration. Our team has access to data from brain-derived extracellular vesicles (EVs) from the same AD cohort as above. Aim 3. To determine the impact of dramatic temperature disruptions on network biology in model organisms. We will utilize the short- lifespan nematode worms (C. elegans) and Killifish (N. furzeri) to study the effects of extreme temperatures on age-associated pathology and lifespan using analogous measures to those used in Aims 1 and 2 allowing a cross-species analysis of temperature-induced changes in biological networks. Completion of these aims will provide a foundation for using multiomic-based network biology to study complex climatic changes on human health and disease contributing to the overall mission of CHART.