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 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.

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 Vesicles: Roles in Human Viral Infections, Immune-Diagnostic, and Therapeutic Applications

“…This could potentially explain why studies on the EV–HIV relationship have revealed key similarities in the pathways involved in their intracellular formation [ 2 , 7 ]. Moreover, EVs such as exosomes, have been shown to play critical roles in disease pathogenesis for a number of viruses, including HIV [ 8 ], human adenovirus (HAdv) [ 9 ], and coronavirus (CoV) [ 10 ]. For instance, HIV is known to exploit the exosomal pathway to generate infectious particles that promote viral spread.…”

HIV-1 Latency and Viral Reservoirs: Existing Reversal Approaches and Potential Technologies, Targets, and Pathways Involved in HIV Latency Studies

“…Antibodies and compounds that target HMG box have been reviewed in detail elsewhere, such as Anti-HMGB1 m2G7, acetylcholine, P5779, and resveratrol, which inhibit the signaling pathways associated with HMGB1 and TLR4 signaling [99][100][101]. Moreover, other HMG box protein-binding molecules, such as the receptor for advanced glycation products (RAGE), revealed a link between HIV infection and TLR4 signaling, and the use of RAGE/HMGB1 inhibitors such as FPS-ZM1 in latency study has already been evaluated [102][103][104][105]. Some of these molecules are potential candidates for future studies on HMG box protein and TOX-mediated HIV latency reversion or upkeep.…”