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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0466-0) contains supplementary material, which is available to authorized users.

Enhanced generation of intraluminal vesicles in neuronal late endosomes in the brain of a Down syndrome mouse model with endosomal dysfunction

“…We previously demonstrated higher level of exosome release into the brain extracellular space of 12‐month‐old Ts2 mice compared to 2N controls (Gauthier et al, ). We have also shown that CD63 mRNA is upregulated in 12‐month‐old Ts2 mouse brains, and CD63 protein levels are higher in Ts2 and DS brains compared to controls and hypothesized that higher level of generation of ILVs leads to the higher level of exosome release (Gauthier et al, ). Here we confirm our hypothesis, demonstrating that trisomic murine neurons at 12 months of age produce more ILVs.…”

“…Here we confirm our hypothesis, demonstrating that trisomic murine neurons at 12 months of age produce more ILVs. Given that exosomes secretion was significantly enhanced also in older Ts2 mice (Gauthier et al, ), it is likely that the higher rate of ILVs formation is maintained with age. We also show that Rab35, that has a prominent role in MVBs fusion with the plasma membrane and release of ILVs via exosomes (Hsu et al, ), is enriched in endosomal/MVBs fractions, corroborating the idea that MVBs in Ts2 mice are more prone to fuse with the plasmalemma and release the cargo when compared to 2N littermates.…”

“…Accordingly, Ts2 mice show a DS‐like phenotype (Jiang et al, ; Kaur et al, ; Levine, Saltzman, Levy, & Ginsberg, ), closely resembling the extensively studied Ts65Dn mouse model, but are more chromosomally stable (Villar et al, ). We have previously demonstrated that while the neuronal endosomal pathology occurs in the brain of Ts2 mice at four months of age (Jiang et al, ), enhanced exosomal release can be detected first at 12 months of age (Gauthier et al, ). Therefore, we investigated Ts2 mice at 12 months of age, demonstrating that they have larger and more abundant MVBs per neuron and higher number of ILVs per MVB when compared to their disomic (2N) controls.…”

“…MVBs are delivered either to the lysosomes for degradation of the cargo or to the plasma membrane where they fuse and release ILVs as exosomes into the extracellular space (Perez‐Gonzalez, Gauthier, Kumar, & Levy, ). Recently, we have demonstrated that in DS, where the endosomal–lysosomal pathway is compromised (Colacurcio, Pensalfini, Jiang, & Nixon, ), the release of exosomes into the extracellular space of human and murine brains is increased (Gauthier et al, ).…”

Exosome release and cargo in Down syndrome

“…As described earlier, individuals with AD and DS have dysfunctions in endosomal transport and endosomal enlargement (Cataldo et al, ; Ginsberg et al, ), a cellular pathology which may be compensated by exosomal secretion. In a recent study, Levy and colleagues support this notion with evidence that post mortem brain tissue isolated from individuals with DS expelled nearly 40% more exosomes that age‐matched non‐DS controls (Gauthier et al, ). They showed that this enhanced exosome secretion phenomenon also occurred in the TS2 mouse model of DS, which also exhibits age‐related endosome abnormalities (Levine, Saltzman, Levy, & Ginsberg, ).…”