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2008 Grants - Hill
Investigating Exosomes as Novel Secretory Carriers of APP and Abeta
Andrew F. Hill, Ph.D.
University of Melbourne
2008 New Investigator Research Grant
Beta-amyloid (Abeta) is a protein fragment created by the cutting of a larger protein, amyloid precursor protein (APP). Beta-amyloid is later secreted from nerve cells and into the fluid space surrounding them, where it aggregates into amyloid plaque, a characteristic feature of Alzheimer pathology.
Complex cellular "machinery" and pathways perform the steps involved in secretion of beta-amyloid and other proteins. One such pathway results in the secretion of exosomes, tiny "bubbles" of cellular material released into the space outside the cell. Andrew F. Hill, Ph.D., and colleagues have recently shown that exosomes may contain (1) APP; (2) beta-amyloid, the final product of APP cleavage; and (3) an intermediate portion of APP known as the C-terminal fragment. They also found evidence that some of the cutting of APP to yield beta-amyloid occurs in the exosome.
Dr. Hill and colleagues plan to perform additional studies of the exosome pathway and its role in the processing and secretion of APP and beta-amyloid. The researchers plan to isolate exosomes from cells and study whether the exosomes can independently process APP. They will also use genetic and biochemical techniques to study the enzymes required for such processing within the exosome. Finally, the researchers will test whether these exosomes are toxic to nerve cells. These studies may advance our understanding of a pathway by which beta-amyloid is secreted and may suggest new therapeutic targets.