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

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 endproducts (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.

Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C‐terminal AAs 2‐5 to mitogen‐activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3‐MKK3‐p38 module assembly

“…In contrast to wild‐type mice, neuronal synaptic plasticity and cognition were relatively well preserved in RAGE −/− mice because of inhibition of the AGEs‐RAGE‐dependent signal transduction pathway (Momeni et al, 2021a; Zhang et al, 2014). Furthermore, the RAGE‐specific inhibitor FPS‐ZM1 reverses the effects of the AGEs‐RAGE system in high‐glucose conditions and dampens p38MAPK and NF‐κB signals (András et al, 2020; Tan et al, 2015; Xie et al, 2013), and ameliorates cognitive dysfunction in STZ‐induced hyperglycemic mice (Momeni et al, 2021b). Our present study identifies the detailed molecular mechanism by which RAGE activates p38MAPK/NF‐κB signaling, thus provides new information on the pathogenesis of DE.…”

Extracellular vesicle-Serpine-1 affects neural progenitor cell mitochondrial functions and synaptic density: modulation by amyloid beta and HIV-1

“…EVs are recognized as important contributors to Aβ pathology [49][50][51][52][53][54][55], including elevated Aβ deposition in HIV-1 infection [20,22]. We have shown previously that EV-Aβ can be transferred to cells of the neurovascular unit, including neural progenitor cells (NPCs) [20]; however, the mechanisms of EVmediated Aβ pathology remain elusive.…”

“…HIV-1 stock was generated using human embryonic kidney (HEK) 293T cells (ATCC) transfected with pYK-JRCSF plasmid containing full-length proviral DNA. Throughout the study, HBMEC were exposed to HIV-1 particles at the p24 level of 30 ng/ml as previously reported [22]. Treatment was terminated by removing cell culture media containing HIV-1, followed by washing the cells with PBS.…”

“…If HEK293T cells were cultured in Exo-FBS, their morphology changed, and the resulting viral stock had vastly different effects on EV release and EV isolation. Therefore, HEK293T cells were cultured in media containing regular FBS consistent with our previous reports [20,22]. As a control for HIV-1 exposure, isolates from mocktransfected HEK293T cells were used.…”

“…Importantly, HBMEC-derived EVs (HBMEC-EVs) carrying Aβ can be transferred to other cells of the neurovascular unit, including neural progenitor cells (NPCs), causing NPC dysfunction and their aberrant neurogenesis [22]. The mechanisms of this EV-mediated Aβ pathology are not clear; however, proteomics of HBMEC-EVs revealed a complex protein cargo with elaborate functional interactions as mapped in STRING [23].…”