Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection.

Amyloid beta (Abeta) deposition was demonstrated to be elevated in the brains of HIV-infected patients and associated with neurocognitive decline; however, the mechanisms of these processes are poorly understood. The goal of the current study was to address the hypothesis that Abeta can be transferred via extracellular vesicles (ECVs) from brain endothelial cells to neural progenitor cells (NPCs) and that this process can contribute to abnormal NPC differentiation. Mechanistically, we focused on the role of the receptor for advanced glycation end products (RAGE) and activation of the inflammasome in these events. ECVs loaded with Abeta (Abeta-ECVs) were readily taken up by NPCs and Abeta partly colocalized with the inflammasome markers ASC and NLRP3 in the nuclei of the recipient NPCs. This colocalization was affected by HIV and RAGE inhibition by a high-affinity specific inhibitor FPS-ZM1. Blocking RAGE resulted also in an increase in ECV number produced by brain endothelial cells, decreased Abeta content in ECVs, and diminished Abeta-ECVs transfer to NPC nuclei. Interestingly, both Abeta-ECVs and RAGE inhibition altered NPC differentiation. Overall, these data indicate that RAGE inhibition affects brain endothelial ECV release and Abeta-ECVs transfer to NPCs. These events may modulate ECV-mediated amyloid pathology in the HIV-infected brain and contribute to the development of HIV-associated neurocognitive disorders.