Enhanced exosome secretion in Down syndrome brain - a protective mechanism to alleviate neuronal endosomal abnormalities

Sébastien A Gauthier,Gurjinder Kaur,Monika Pawlik,Thomas A Neubert,Rocío Pérez-González,Fang-Ke Huang,Efrat Levy,Stephen D Ginsberg,Melissa J Alldred,Ajay Sharma

doi:10.1186/s40478-017-0466-0

Abstract

A dysfunctional endosomal pathway and abnormally enlarged early endosomes in neurons are an early characteristic of Down syndrome (DS) and Alzheimer’s disease (AD). We have hypothesized that endosomal material can be released by endosomal multivesicular bodies (MVBs) into the extracellular space via exosomes to relieve neurons of accumulated endosomal contents when endosomal pathway function is compromised. Supporting this, we found that exosome secretion is enhanced in the brains of DS patients and a mouse model of the disease, and by DS fibroblasts. Furthermore, increased levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Importantly, CD63 knockdown diminished exosome release and worsened endosomal pathology in DS fibroblasts. Taken together, these data suggest that increased CD63 expression enhances exosome release as an endogenous mechanism mitigating endosomal abnormalities in DS. Thus, the upregulation of exosome release represents a potential therapeutic goal for neurodegenerative disorders with endosomal pathology.

Highlights

A dysfunctional endosomal pathway and abnormally numerous and enlarged early endosomes are found within vulnerable Alzheimer’s disease (AD) neurons early in life [7]
Separation of the extracellular vesicles (EVs) on a sucrose gradient resulted in 7 fractions, from a, the least dense, to g, the densest fraction, and Western-blot analysis showed that fractions with densities higher than 1.07 and lower than 1.17 were immunoreactive to Flotillin-1 and Flotillin-2, lipid raft proteins found in EVs, and established exosomal markers (Fig. 1a)
We measured the levels of exosome-enriched EVs by quantifying the activity of Acetylcholine esterase (AChE), a protein that is sorted into exosomes [27, 46]

Summary

Introduction

A dysfunctional endosomal pathway and abnormally numerous and enlarged early endosomes are found within vulnerable Alzheimer’s disease (AD) neurons early in life [7]. These characteristics are seen in Down syndrome (DS) [10], a genetic disorder caused by trisomy of human chromosome 21 that leads to earlyonset AD [55]. Endosomes are the first vesicular compartment along the endocytic pathway, which internalizes cargoes for delivery to late endosomes/multivesicular bodies (MVBs) for either degradation in lysosomes or for release into the extracellular space via exosomes. ILVs formation is regulated by the endosomal sorting complexes required for transport (ESCRT)

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Discussion

Conclusion