Abstract
BackgroundMaintaining an intact pool of neural progenitor cells (NPCs) is crucial for generating new and functionally active neurons. As intrinsic and microenvironments tightly control developmental processes of adult neurogenesis, Methamphetamine (METH) and HIV-1-mediated impairment of the blood-brain barrier and development of neuroinflammation may induce alterations in functions of NPCs; however, the combined effects of METH and HIV-1 on the NPCs are still poorly understood.MethodsTo elucidate the possible mechanisms for the enhanced proliferation of NPCs by METH exposure and HIV infection, Male C57BL/6 mice were injected with METH with an escalating dose regimen for 6 days, followed by infusion with a chimeric HIV-NDK (EcoHIV) into the left internal carotid artery to infect brains. NPCs were isolated from the subventricular zone (SVZ) and used for RNA sequencing and differential expression analysis two weeks after infection. ReNcell VM, an immortalized human NPC line were used for in vitro exposure to METH and HIV infectionResultsChronic exposure to METH combined with brain infection by EcoHIV enhanced the proliferation of NPCs in the SVZ in mice. This effect was long-lasting as it was preserved ex vivo in NPCs isolated from the exposed mice over several passages in the absence of additional treatments. Transcriptomic studies indicated that 27 out of the top 30 differentially expressed genes response to METH plus EcoHIV were targets of the Forkhead box O transcriptional factor (FOXO), and primarily FOXO3. Additional ex vivo studies and in vitro experiments revealed the upregulation of the CXCL12-CXCR4 axis, leading to activation of downstream pAkt and pErk, the pathways that can phosphorylate FOXO3 and force its exports from the nuclei into the cytoplasm. Indeed, nuclear expulsion of FOXO3 was demonstrated both in mice exposed to METH and infected with EcoHIV and in cell culture of human NPCs.ConclusionsThese results provide novel information that exposure to METH combined with HIV infection can induce aberrant proliferation of SVZ-derived NPCs. Upregulation of CXCL12-CXCR4-Akt-1 signaling pathway exported FOXO3 into the cytoplasm, which changed the mRNA expression of FOXO3-target genes and induced the proliferation alteration as a result.
Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection
