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Cell Mol Life Sci. 2018 Feb;75(4):757-773. doi: 10.1007/s00018-017-2664-0. Epub 2017 Sep 27.

Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons.

Author information

1
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, 38042, Grenoble, France. klaulagn@gmail.com.
2
Institut des Neurosciences, Université Grenoble Alpes, 38042, Grenoble, France. klaulagn@gmail.com.
3
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, 38042, Grenoble, France.
4
Institut des Neurosciences, Université Grenoble Alpes, 38042, Grenoble, France.
5
Dulbecco Telethon Institute Lab of Neurodegenerative Diseases, Centre for Integrative Biology (CIBIO), University of Trento, 38123, Trento, Italy.
6
Institut National de la Santé et de la Recherche Médicale (INSERM), U1216, 38042, Grenoble, France. remy.sadoul@univ-grenoble-alpes.fr.
7
Institut des Neurosciences, Université Grenoble Alpes, 38042, Grenoble, France. remy.sadoul@univ-grenoble-alpes.fr.

Abstract

Amyloid beta peptide (Aβ), the main component of senile plaques of Alzheimer's disease brains, is produced by sequential cleavage of amyloid precursor protein (APP) and of its C-terminal fragments (CTFs). An unanswered question is how amyloidogenic peptides spread throughout the brain during the course of the disease. Here, we show that small lipid vesicles called exosomes, secreted in the extracellular milieu by cortical neurons, carry endogenous APP and are strikingly enriched in CTF-α and the newly characterized CTF-η. Exosomes from N2a cells expressing human APP with the autosomal dominant Swedish mutation contain Aβ peptides as well as CTF-α and CTF-η, while those from cells expressing the non-mutated form of APP only contain CTF-α and CTF-η. APP and CTFs are sorted into a subset of exosomes which lack the tetraspanin CD63 and specifically bind to dendrites of neurons, unlike exosomes carrying CD63 which bind to both neurons and glial cells. Thus, neuroblastoma cells secrete distinct populations of exosomes carrying different cargoes and targeting specific cell types. APP-carrying exosomes can be endocytosed by receiving cells, allowing the processing of APP acquired by exosomes to give rise to the APP intracellular domain (AICD). Thus, our results show for the first time that neuronal exosomes may indeed act as vehicles for the intercellular transport of APP and its catabolites.

KEYWORDS:

CTF-C83; CTF-C99; Extracellular vesicles; Intercellular communication; Neurodegenerative disorders

PMID:
28956068
DOI:
10.1007/s00018-017-2664-0

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