Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons

Polanco, Juan Carlos, Li, Chuanzhou, Durisic, Nela, Sullivan, Robert and Götz, Jürgen (2018) Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons. Acta Neuropathologica Communications, 6 1: 1-14. doi:10.1186/s40478-018-0514-4

Author Polanco, Juan Carlos
Li, Chuanzhou
Durisic, Nela
Sullivan, Robert
Götz, Jürgen
Title Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons
Journal name Acta Neuropathologica Communications   Check publisher's open access policy
ISSN 2051-5960
Publication date 2018-02-15
Year available 2018
Sub-type Article (original research)
DOI 10.1186/s40478-018-0514-4
Open Access Status DOI
Volume 6
Issue 1
Start page 1
End page 14
Total pages 14
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Abstract In Alzheimer disease and related disorders, the microtubule-associated protein tau aggregates and forms cytoplasmic lesions that impair neuronal physiology at many levels. In addition to affecting the host neuron, tau aggregates also spread to neighboring, recipient cells where the misfolded tau aggregates, in a manner similar to prions, actively corrupt the proper folding of soluble tau, and thereby impair cellular functions. One vehicle for the transmission of tau aggregates are secretory nanovesicles known as exosomes. Here, we established a simple model of a neuronal circuit using a microfluidics culture system in which hippocampal neurons A and B were seeded into chambers 1 and 2, respectively, extending axons via microgrooves in both directions and thereby interconnecting. This system served to establish two models to track exosome spreading. In the first model, we labeled the exosomal membrane by coupling tetraspanin CD9 with either a green or red fluorescent tag. This allowed us to reveal that interconnected neurons exchange exosomes only when their axons extend in close proximity. In the second model, we added exosomes isolated from the brains of tau transgenic rTg4510 mice (i.e. exogenous, neuron A-derived) to neurons in chamber 1 (neuron B) interconnected with neuron C in chamber 2. This allowed us to demonstrate that a substantial fraction of the exogenous exosomes were internalized by neuron B and passed then on to neuron C. This transportation from neuron B to C was achieved by a mechanism that is consistent with the hijacking of secretory endosomes by the exogenous exosomes, as revealed by confocal, super-resolution and electron microscopy. Together, these findings suggest that fusion events involving the endogenous endosomal secretory machinery increase the pathogenic potential and the radius of action of pathogenic cargoes carried by exogenous exosomes.
Keyword Alzheimer
Axonal transport
Organelle fusion
Protein aggregates
Spreading, Exosomes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
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Created: Wed, 21 Feb 2018, 11:04:39 EST