Amyloid-β Reduces Exosome Release from Astrocytes by Enhancing JNK Phosphorylation

Exosomes are small extracellular vesicles secreted by variety of cell types such as neurons, astrocytes, and oligodendrocytes. It is suggested that exosomes play essential role in the maintenance of the neuronal functions and also in the clearance of amyloid-beta (A beta) from the brain. beta is well known to cause neuronal cell death, whereas little is known about its effect on astrocytes. In this study, we examined the effect of A beta on release of exosomes from astrocytes in culture. We analyzed release of exosomes and apoE, both of which are known to remove/clear A beta from the brain, in the culture medium of astrocytes. We found that exosome and apo E-HDL were successfully separated by density gradient ultracentrifugation demonstrated by distribution of their specific markers, flotillin and HSP90, and cholesterol, and morphological analysis using electron microscopy. Exosome release was significantly reduced by A beta(1-42) treatment in cultured astrocytes accompanied by an increased JNK phosphorylation. Whereas, apo E-HDL release remained unchanged. A JNK inhibitor restored the decreased levels of exosome release induced by A beta treatment to levels similar to those of control, suggesting that A beta 1-42 inhibits exosome release via stimulation of JNK signal pathway. Because exosomes are shown to remove A beta in the brain, our findings suggest that increased A beta levels in the brain may impair the exosome-mediated A beta clearance pathway.