Methamphetamine and HIV-1 Tat down regulate β-catenin signaling: implications for methampetamine abuse and HIV-1 co-morbidity.

Abstract

Methamphetamine (Meth) abuse exacerbates HIV-1-associated neurocognitive disorders (HAND). The underlying mechanism for this effect is not entirely clear but likely involves cooperation between Meth and HIV-1 virotoxins, such as the transactivator of transcription, Tat. HIV-1 Tat mediates damage in the CNS by inducing inflammatory processes including astrogliosis. Wnt/β-catenin signaling regulates survival processes for both neurons and astrocytes. Here, we evaluated the impact of Meth on the Wnt/β-catenin pathway in astrocytes transfected with Tat. Meth and Tat downregulated Wnt/β-catenin signaling by >50%, as measured by TOPflash reporter activity in both an astrocytoma cell line and primary human fetal astrocytes. Meth and Tat also downregulated LEF-1 transcript by >30%. LEF-1 is a key partner of β-catenin to regulate cognate gene expression. Interestingly, estrogen, which induces β-catenin signaling in a cell-type specific manner, at physiological concentrations of 1.5 and 3 nM normalized individual Meth and Tat effects on β-catenin signaling but not their combined effects. These findings suggest that Meth and Tat likely exert different mechanisms to mediate down regulation of β-catenin signaling. The consequences of which may contribute to the pathophysiologic effects of HIV-1 and Meth co-morbidity in the CNS.

• Authors: Amit Sharma, Xiu-Ti Hu, T Celeste Napier, Lena Al-Harthi
• Journal: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology (J Neuroimmune Pharmacol) Vol. 6 Issue 4 Pg. 597-607 (Dec 2011) ISSN: 1557-1904 [Electronic] United States
• PMID: 21744004 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CTNNB1 protein, human
• Central Nervous System Stimulants
• Illicit Drugs
• beta Catenin
• tat Gene Products, Human Immunodeficiency Virus
• Methamphetamine

Topics

• AIDS Dementia Complex (metabolism, virology)
• Astrocytes (drug effects, metabolism, virology)
• Cell Line
• Central Nervous System Stimulants (pharmacology)
• Comorbidity
• Down-Regulation
• HIV Infections (epidemiology, virology)
• HIV-1
• Humans
• Illicit Drugs (pharmacology)
• Methamphetamine (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Substance-Related Disorders (epidemiology, virology)
• beta Catenin (metabolism)
• tat Gene Products, Human Immunodeficiency Virus (metabolism)