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The Exosome Secretory Pathway Transports Amyloid Precursor Protein Carboxyl-terminal Fragments from the Cell into the Brain Extracellular Space

In vitro studies have shown that neuronal cell cultures secrete exosomes containing amyloid-β precursor protein (APP) and the APP-processing products, C-terminal fragments (CTFs) and amyloid-β (Aβ). We investigated the secretion of full-length APP (flAPP) and APP CTFs via the exosome secretory pathw...

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Bibliographic Details
Published in:The Journal of biological chemistry 2012-12, Vol.287 (51), p.43108-43115
Main Authors: Perez-Gonzalez, Rocio, Gauthier, Sebastien A., Kumar, Asok, Levy, Efrat
Format: Article
Language:English
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Summary:In vitro studies have shown that neuronal cell cultures secrete exosomes containing amyloid-β precursor protein (APP) and the APP-processing products, C-terminal fragments (CTFs) and amyloid-β (Aβ). We investigated the secretion of full-length APP (flAPP) and APP CTFs via the exosome secretory pathway in vivo. To this end, we developed a novel protocol designed to isolate exosomes secreted into mouse brain extracellular space. Exosomes with typical morphology were isolated from freshly removed mouse brains and from frozen mouse and human brain tissues, demonstrating that exosomes can be isolated from post-mortem tissue frozen for long periods of time. flAPP, APP CTFs, and enzymes that cleave both flAPP and APP CTFs were identified in brain exosomes. Although higher levels of both flAPP and APP CTFs were observed in exosomes isolated from the brains of transgenic mice overexpressing human APP (Tg2576) compared with wild-type control mice, there was no difference in the number of secreted brain exosomes. These data indicate that the levels of flAPP and APP CTFs associated with exosomes mirror the cellular levels of flAPP and APP CTFs. Interestingly, exosomes isolated from the brains of both Tg2576 and wild-type mice are enriched with APP CTFs relative to flAPP. Thus, we hypothesize that the exosome secretory pathway plays a pleiotropic role in the brain: exosome secretion is beneficial to the cell, acting as a specific releasing system of neurotoxic APP CTFs and Aβ, but the secretion of exosomes enriched with APP CTFs, neurotoxic proteins that are also a source of secreted Aβ, is harmful to the brain. Background: Exosomes isolated in vitro contain full-length amyloid-β precursor protein (flAPP) and APP metabolites. Results: Exosomes secreted in vivo in brains of wild-type and APP-overexpressing mice contain higher levels of APP C-terminal fragments (CTFs) relative to flAPP compared with brain tissue. Conclusion: Brain exosomes are enriched with APP CTFs. Significance: The exosome secretory pathway clears cellular APP CTFs, releasing the toxic fragments into the neuropil.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.404467