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.
Highlights
Human immunodeficiency virus type 1 (HIV)-infected brains were shown to have increased amyloid beta (Aβ) deposition [1,2,3,4,5,6]
Based on the observations that a) HIV can increase receptor for advanced glycation end products (RAGE) expression in brain endothelial cells [14], b) HIVinduces Amyloid beta (Aβ) accumulation in brain endothelial cells via a RAGE-dependent mechanism [14], and c) RAGE may be involved in microvesicle secretion [27], we hypothesize in the current study that RAGE may be a key player in the HIV-induced brain endothelial extracellular vesicles (ECVs) release and AβECVs transfer to neural progenitor cells (NPCs). Because both HIV infection [28] and Aβ pathology [29, 30] were linked to the inflammasome pathway, and RAGE was shown to signal through the NLR family pyrin domain containing 3 (NLRP3) inflammasome [31], we further aimed to examine the impact of Aβ-ECV transfer on the NLRP3 inflammasome in NPCs
The RAGE pathway may both interfere with ECV release, as it was shown in macrophages [27], and with Aβ accumulation in brain endothelial cells [14]
Summary
HIV-infected brains were shown to have increased amyloid beta (Aβ) deposition [1,2,3,4,5,6]. Aβ deposition occurs mostly in the perivascular space [3, 7,8,9], which points to the brain microvessels having a role in amyloid pathology. In support of this notion, the blood-brain barrier (BBB), a critical player in the brain infection by HIV and the development of HIV-associated cerebrovascular comorbidities [10, 11], was postulated to regulate Aβ homeostasis as an interface contributing to Aβ. We observed that HIV increased the shedding of ECVs carrying Aβ from brain endothelial cells. ~ 47% of dividing progenitor and 46% of transit amplifying cells
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