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SELECTBIO Conferences Extracellular Vesicles 2023: Drug Delivery, Biologics & Therapeutics


Extracellular Vesicle-Mediated Amyloid Transfer and Intercellular Communication within the Neurovascular Unit

Michal Toborek, Professor and Vice-Chair for Research, University of Miami School of Medicine

It is widely accepted that elevated brain deposits of amyloid beta (A-beta) contribute to neuropathology in Alzheimer’s disease. Additionally, A-beta deposition was demonstrated to be elevated in the brains of HIV-infected patients and associated with neuro-cognitive decline; however, the mechanisms of these processes are poorly understood. The role of the blood-brain barrier (BBB) as an interface for the transfer of A-beta from the periphery into the brain and the cells of neurovascular unit is poorly characterized. Indeed, substantial population of neural progenitor cells (NPC) reside near brain capillaries that form the BBB. The purpose of this study is to understand the impact of brain endothelium-derived extracellular vesicles containing A-beta (A-beta-EVs) on metabolic functions and differentiation of NPCs. Mechanistically, we focused on the role of mitochondria, the receptor for advanced glycation end products (RAGE), and activation of the inflammasome on these events. We demonstrate that physiological concentrations of A-beta-40 can transfer and accumulate in NPCs via endothelial EVs. This transfer results in mitochondrial dysfunction, disrupting cristae morphology, metabolic rates, fusion and fission dynamics of NPCs, as well as their neurite development. Moreover, our results show that A-beta partly co-localized with the inflammasome markers ASC and NLRP3 in the recipient NPCs. This co-localization was affected by HIV and RAGE inhibition by a high-affinity specific inhibitor, FPS-ZM1. Interestingly, both A-beta-EVs and RAGE inhibition altered NPC differentiation. Overall, our data indicates that intercellular transfer of A-beta-40 is carried out by brain endothelium derived EVs that can induce mitochondrial dysfunction and alter cellular signaling, leading to aberrant neurogenesis of NPCs. These events may modulate EV-mediated amyloid pathology in the HIV-infected brain and contribute to the development of HIV-associated neuro-cognitive disorders.

Add to Calendar ▼2023-07-26 00:00:002023-07-27 00:00:00Europe/LondonExtracellular Vesicles 2023: Drug Delivery, Biologics and TherapeuticsExtracellular Vesicles 2023: Drug Delivery, Biologics and Therapeutics in Orlando, FloridaOrlando,