Exosomes and are virus-sized extracellular vesicles that are released from many cell types including neurons. Exosomes are being developed for various clinical and translational applications such as biomarkers of disease and drug delivery vehicles. Evidence suggests they play a role in the progression of Alzheimer's disease (AD) through the transport of pathogenic proteins associated with the disease. Despite rapid advances in the field, there is still a limited understanding of many aspects of exosome biology in AD, including their formation, cargo selection, and role in cell-to-cell communication and disease propagation. In order to clarify the role of exosomes in AD and develop novel therapeutics to combat this devastating disease, a more complete understanding of exosome biology is needed. Here, we seek to clarify the mechanisms of exosome biogenesis and protein trafficking that contribute to amyloid precursor protein (APP) and amyloid beta (A?) exosomal incorporation and plaque deposition in the brain. From the preliminary data, our overall hypothesis is that amyloidogenic APP modulates the components and biological properties of exosomes secreted from neuronal cells, and that these changes contribute to AD pathology and disease progression through neurotoxic and inflammatory responses. To test this we will; 1) determine the mechanism of APP and A? exosomal packaging and secretion; 2) identify the changes in exosome cargo due to mutant APP processing and exosomal trafficking. Overall, the completion of this study will provide novel insight into the mechanisms controlling exosome biogenesis, content, functions, and protein trafficking during mutant APP processing and A? exosomal accumulation.
RESEARCH NARRATIVE Exosomes are small, membrane-enclosed sacs released by all cell types including diseased neurons. Exosomes contain proteins associated with the development and progression of Alzheimer's disease. Therefore, a better understanding of exosome cargo and the mechanisms of their biogenesis and incorporation of diseased proteins will aid in the development of new therapeutics to combat Alzheimer's disease.
