Methamphetamine Enhances HIV-Induced Aberrant Proliferation of Neural Progenitor Cells via the FOXO3-Mediated Mechanism

Minseon Park,Darya Pavlenko,William Baker,Schuyler Van Den Nieuwenhuizen,Michal Toborek,Bridget Herlihy,Ana Rachel Leda,Danielle Gogerty,Dilraj Cambow

doi:10.1007/s12035-021-02407-9

Abstract

Maintaining an intact pool of neural progenitor cells (NPCs) is crucial for generating new and functionally active neurons. Methamphetamine (METH) can exacerbate the HIV-induced deficit of adult neurogenesis; however, potential mechanisms of this influence are still poorly understood. In the present study, we present evidence that chronic exposure to METH combined with brain infection by EcoHIV results in enhanced proliferation of NPCs in the subventricular zone (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. Increased proliferation in response to METH plus HIV was associated with dysregulation of cyclin B1 and cyclin D. Transcriptomic studies indicated that 27 out of the top 30 differentially expressed genes in 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 using human NPCs exposed to METH and infected with HIV revealed 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 cultures of human NPCs. These results provide novel information that exposure to METH combined with HIV infection can induce aberrant proliferation of SVZ-derived NPCs and identifies CXCL12-CXCR4-Akt-1-mediated phosphorylation of FOXO3 as the mechanism responsible for this effect.

Highlights

Methamphetamine (METH) use disorder is a global health problem affecting over 35 million users worldwide
The findings indicate that exposure to METH combined with HIV infection exerts a long-term impact on neural progenitor cells (NPCs) transcriptomics that is preserved ex vivo and results in enhanced NPC proliferation via the CXCL12/CXCR4/Akt-1-mediated phosphorylation of FOXO3 that regulates FOXO3 target genes
Total RNA was extracted from subventricular zone (SVZ)-derived NPCs using RNeasy Mini Kit (Qiagen), digested with RNAse-free DNAse I (Epicentre), and purified using RNeasy MinElute columns (Qiagen). cDNA libraries were constructed from DNA-free total RNA (50 ng) using the Universal Plus mRNA-Seq Library Prep Kit (NuGEN Technologies), followed by loading onto an Illumina NextSeq 500 v2.5 flow cell cartridge

Summary

Introduction

Methamphetamine (METH) use disorder is a global health problem affecting over 35 million users worldwide. While it was reported that human hippocampal neurogenesis is diminished in adult humans [9], others observed that this process persists throughout aging [10, 11], and healthy older men and women produce just as many new neurons as younger people [11]. Functional neurons, neural stem cells (NSCs), and their progeny, NPCs, undergo developmental processes that are tightly controlled by intrinsic and niche-derived morphogens, neurotransmitters, growth factors, and cytokines [12]. METH- and HIV-1-mediated impairment of the blood-brain barrier [13] and the development of neuroinflammation [14] may induce microenvironmental changes altering the function and neurogenesis of neural stem/progenitor cells

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