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

Ibolya E. András, Marta Garcia-Contreras, Christopher Yanick, Paola Perez, Brice Sewell, Leonardo Durand, Michal Toborek

Research output: Contribution to journalArticle

Abstract

Amyloid beta (Aβ) 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 Aβ 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 Aβ (Aβ-ECVs) were readily taken up by NPCs and Aβ 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 Aβ content in ECVs, and diminished Aβ-ECVs transfer to NPC nuclei. Interestingly, both Aβ-ECVs and RAGE inhibition altered NPC differentiation. Overall, these data indicate that RAGE inhibition affects brain endothelial ECV release and Aβ-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.

Original languageEnglish (US)
Article number21
JournalMolecular Brain
Volume13
Issue number1
DOIs
StatePublished - Feb 17 2020

Keywords

  • Amyloid beta
  • Blood-brain barrier
  • Extracellular vesicles
  • Neural progenitor cells
  • RAGE

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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