There is growing recognition that cell non-autonomous signals play a major role in both normative aging and in Alzheimer?s Disease (AD); however, the mechanisms underlying these processes remain largely unknown. Extracellular vesicles (ECVs) represent a major system for the transduction of cell non-autonomous signals as well as a pathological macromolecule integral to Alzheimer?s disease, including misfolded or aggregation-prone proteins and peptides. However, there is is no simple genetic model by which the physiology of these processes can be studied. I propose to develop the nematode Caenorhabditis elegans as a powerful model for the study of ECV signaling in normative aging and Alzheimer?s disease. In this proposal I will (1) determine the physiological relevance of nematode ECV signaling in cell non-autonomous mechanisms of longevity determination (2) uncover the role of ECV-signaling in spreading A 1-42 from cell to cell (3) and compare the effects of normative aging and AD on the abundance and compositions of ECVs from C. elegans ECVs and human patient cerebrospinal fluid samples. These studies will leverage the resources of both the UW Nathan Shock Center of Excellence in the Basic Biology of Aging as well as the UW Alzheimer?s Disease Research Center to provide key insights into the composition of ECVs from both C. elegans and AD patients, and will set the stage for a detailed mechanistic understanding of the effect of aging on ECV function and the role of ECVs in aging and Alzheimer?s disease.

Public Health Relevance

PHS Fellowship Supplemental Form 8. Project Narrative There is growing evidence that extracellular vesicle (ECV) signaling plays major roles in both aging and the progression of Alzheimer?s Disease; however, how it does this remains a mystery because there is is no simple genetic model in which these processes can be investigated. This study proposes to pioneer the study of ECVs in aging and Alzheimer?s disease using the nematode Caenorhabditis elegans, one of the most widely utilized model organisms, and compare these results with human AD patient samples. These studies will provide key insights into the composition of ECVs from both nematodes and AD patients, providing a new paradigm for developing therapeutics that extend healthy lifespans and treat Alzheimer?s disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Yang, Austin Jyan-Yu
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University of Washington
Schools of Medicine
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Bennett, Christopher F; Kwon, Jane J; Chen, Christine et al. (2017) Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans. PLoS Genet 13:e1006695
Russell, Joshua Coulter; Burnaevskiy, Nikolay; Ma, Bridget et al. (2017) Electrophysiological measures of aging pharynx function in C. elegans reveal enhanced organ functionality in older, long-lived mutants. J Gerontol A Biol Sci Med Sci :