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Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction
Jonathan Pitcher, … , Jay Rappaport, Olimpia Meucci
Jonathan Pitcher, … , Jay Rappaport, Olimpia Meucci
Published January 9, 2014
Citation Information: J Clin Invest. 2014;124(2):656-669. https://doi.org/10.1172/JCI70090.
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Research Article AIDS/HIV Article has an altmetric score of 11

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

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Abstract

Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.

Authors

Jonathan Pitcher, Anna Abt, Jaclyn Myers, Rachel Han, Melissa Snyder, Alessandro Graziano, Lindsay Festa, Michele Kutzler, Fernando Garcia, Wen-Jun Gao, Tracy Fischer-Smith, Jay Rappaport, Olimpia Meucci

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Figure 5

Regulation of the CXCR4 axis alters the frequency and amplitude of EPSCs of layer II/III pyramidal neurons.

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Regulation of the CXCR4 axis alters the frequency and amplitude of EPSCs...
(A) AMD3100 injection i.c.v. had no effect on sEPSC frequency or amplitude (sample data not shown). (B) Sample traces of mEPSCs recorded at –70 mV in the presence of tetrodotoxin (1 μM) and picrotoxin (100 μM) in layer II/III pyramidal neurons from vehicle- and AMD3100-exposed animals. Quantification revealed AMD3100 exposure significantly decreased mEPSC frequency, but not amplitude. (C) Incubation of prefrontal cortical slices with CXCL12 (20 nM, 3 hours) induced no change in sEPSC frequency, but significantly increased sEPSC amplitude (sample data not shown). (D) Sample traces of mEPSCs recorded at –70 mV in the presence of tetrodotoxin (1 μM) and picrotoxin (100 μM) in layer II/III pyramidal neurons from vehicle- and CXCL12-exposed slices. Quantification revealed CXCL12 exposure had no significant effect on mEPSC frequency or amplitude. *P < 0.04; #P < 0.03.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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