Extracellular Vesicle-Serpine-1 Affects Neural Progenitor Cell Mitochondrial Networks and Synaptic Density: Modulation by Amyloid Beta and HIV-1

Abstract

Brain endothelial extracellular vesicles carrying amyloid beta (EV-Aβ) can be transferred to neural progenitor cells (NPCs) leading to NPC dysfunction. However, the events involved in this EV-mediated Aβ pathology are unclear. EV-proteomics studies identified Serpine-1 (plasminogen activator inhibitor 1, PAI-1) as a major connecting “hub” on several protein–protein interaction maps. Serpine-1 was described as a key player in Aβ pathology and was linked to HIV-1 infection as well. Therefore, the aim of this work was to address the hypothesis that Serpine-1 can be transferred via EVs from brain endothelial cells (HBMEC) to NPCs and contribute to NPC dysfunction. HBMEC concentrated and released Serpine-1 via EVs, the effect that was potentiated by HIV-1 and Aβ. EVs loaded with Serpine-1 were readily taken up by NPCs, and HIV-1 enhanced this event. Interestingly, a highly specific Serpine-1 inhibitor PAI039 increased EV-Aβ transfer to NPCs in the presence of HIV-1. PAI039 also partially blocked mitochondrial network morphology alterations in the recipient NPCs, which developed mainly after HIV + Aβ-EV transfer. PAI039 partly attenuated HIV-EV-mediated decreased synaptic protein levels in NPCs, while increased synaptic protein levels in NPC projections. These findings contribute to a better understanding of the complex mechanisms underlying EV-Serpine-1 related Aβ pathology in the context of HIV infection. They are relevant to HIV-1 associated neurocognitive disorders (HAND) in an effort to elucidate the mechanisms of neuropathology in HIV infection.

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

“…SERPINE1 may play a role in neurodegeneration/neuroprotection via extracellular matrix remodelling, excitotoxicity, blood-brain barrier opening, and recruitment and activation of microglia [30], while secretion of SERPINE2 by astroglia/oligodendroglia at the axoglial junction is believed to regulate nodal length and myelin structure in the optic nerve and corpus callosum [13]. Aberrant expression of SERPINE1 has been linked to neurodegenerative diseases, including Alzheimer’s [1, 27], Parkinson’s disease [57], and MS [28]. Serpinopathies, e.g., ALS (with SERPINE2 accumulation), are characterized by neuronal inclusion bodies that accumulate within the ER and elicit an ER overload response and cell death signalling, [10, 30, 43, 52].…”

Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation

“…SERPINE1 is an important SASP factor [ 41 , 42 ]. In recent years, SERPINE1 has been observed to be enriched in EVs from malignant ascites, glioblastoma cells, and brain endothelial cells [ 43 – 45 ]. Here we reported for the first time that SERPINE1 was transferred from STCs to non-STCs via EVs, thereby contributing to tumor progression.…”