Oral Presentation Australasian Extracellular Vesicles Conference 2018

Unravelling How Exosomes Induce and Propagate Tau Pathology (#43)

Juan Carlos Polanco 1 , Chuanzhou Li 1 , Adam Briner 1 , Jurgen Gotz 1
  1. Clem Jones Centre for Ageing and Dementia Research (CJCADR), Queensland Brain Institute (QBI), The University of Queensland, St Lucia, QLD 4072, Australia

The microtubule-associated protein tau has a critical role in Alzheimer disease. It is well accepted in the field that extracellular tau aggregates spread trans-synaptically, causing tau pathology in recipient neurons. Accordingly, we were the first to demonstrate that tau seeds are found within exosomes isolated from brains of rTg4510 mice, and that only cells undergoing intracellular tau aggregation release exosomes containing tau seeds, which have the ability to induce tau misfolding and aggregation in naïve cells (Polanco et al., JBC 2016). More recently, we showed that exosomes hijack the endosomal pathway to spread through interconnected neurons (Polanco et al., Acta Neuropathol Commun 2018). In my presentation, I will show how internalized exosomes exploit mechanisms of lysosomal degradation to escape the endosomes and induce tau aggregation in the cytosol. By adding exosomal preparations from the brains of rTg4510 and control mice to tau biosensor cells and mouse hippocampal neurons, we found that although the exosomes fused with lysosomes, this did not lead to the elimination of the exosomal tau seeds but rather triggered robust tau aggregation. Overexpression of RAB7, which is required for the fusion of late endosomes with lysosomes, strongly increased tau aggregation. Conversely, inhibition of lysosomal function with alkalinizing agents, or by knocking-down RAB7, decreased tau aggregation. Endolysosomes containing either wild-type or rTg4510-derived exosomes were membrane-permeabilized as demonstrated by the formation of galentin punctae. We conclude that the enzymatic activities of lysosomes permeabilize the exosomal and endosomal membranes, facilitating access of exosomal tau seeds to cytosolic tau.Our data underscore the importance of endosomes in mechanisms of cellular invasion by aggregated proteins that are resistant to lysosomal degradation.