HIV Tat-activated microglial extracellular vesicles induce neuronal iron dysregulation and synaptodendritic injury

作者：Deshetty UM, Martínez-Cuevas FL, Chettiar P, Dravid SM, Periyasamy P, Sil S, Buch S · 发表于：Cell communication and signaling : CCS · 年份：2026 · DOI：10.1186/s12964-026-03032-6 · 研究领域：Extracellular vesicles、HIV-1 Tat、Iron dysregulation、Mitochondrial dysfunction、Synaptodegeneration

Extracellular vesicles (EVs) are membrane-enclosed, nanoscale structures released by cells and play a key role in intercellular communication under both normal physiological and pathological conditions. They serve as conduits for transferring molecular cargo between neighboring cells, thereby modulating recipient cell function. While the HIV Transactivator of transcription (Tat) protein has been shown to induce ferroptosis in microglia, the role of Tat-activated microglia-derived EVs (Tat-MEVs) in transferring iron-handling and ferroptosis-associated cargo to neurons and promoting neuronal injury remains unexplored. In this study, we sought to evaluate the impact of cargo derived from Tat-MEVs on neuronal synaptodendritic degeneration. Rat primary cortical and hippocampal neurons were exposed to either control MEVs or Tat-MEVs and subsequently assessed for synaptodendritic degeneration, expression of key ferroptotic mediators, and mitochondrial dysfunction associated with neuronal injury. Neurons exposed to Tat-MEVs demonstrated increased expression of the key iron-handling and ferroptosis-associated proteins (transferrin, TF; transferrin receptor 1, TFR1; Six-Transmembrane Epithelial Antigen of the Prostate 3, STEAP3; divalent metal transporter 1, DMT1; and ferritin heavy chain 1, FTH1); inhibitory synaptic markers (GAD65, Gephyrin), Fe2+/total iron content, neuronal cytotoxicity and mitochondrial reactive oxygen species (ROS) compared to neurons exposed to control MEVs. The...