Perturbation of Sphingolipid Metabolism and Ceramide Production in HIV-Dementia

Norman Haughey, Roy G. Cutler, Anita Tamara, Justin Charles McArthur, Diana L. Vargas, Carlos A Pardo-Villamizar, Jadwiga Turchan, Avindra Nath, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Infection by the human immunodeficiency virus type 1 (HIV-1) often results in neurological dysfunction including HIV dementia (HIVD). Alterations in cytokine and redox balance are thought to play important roles in the pathogenesis of HIVD, but the specific mechanisms underlying neuronal dysfunction and death are unknown. Activation of cytokine receptors and oxidative stress can induce the production of ceramide from membrane sphingomyelin, and recent findings suggest that ceramide is an important mediator of a form of programmed cell death called apoptosis. We now report that levels of ceramide, sphingomyelin, and hydroxynonenal (HNE) are significantly increased in brain tissues and cerebrospinal fluid of HIVD patients. Exposure of cultured neurons to the neurotoxic HIV proteins gp120 and Tat resulted in increased cellular levels of sphingomyelin, ceramide, and HNE. The ceramide precursor palmitoyl-CoA sensitized neurons to Tat and gp120 toxicity, whereas an inhibitor of ceramide production reduced Tat and gp120-induced increases of ceramide and HNE and protected the neurons from Tat and gp120-induced death. These results suggest that HIV-1 infection may promote a lipid imbalance in neural cells, resulting in an overproduction of ceramide and consequent cellular dysfunction and death.

Original languageEnglish (US)
Pages (from-to)257-267
Number of pages11
JournalAnnals of Neurology
Volume55
Issue number2
DOIs
StatePublished - Feb 2004

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AIDS Dementia Complex
Sphingolipids
Ceramides
Sphingomyelins
Neurons
HIV-1
Human Immunodeficiency Virus tat Gene Products
Palmitoyl Coenzyme A
Cytokine Receptors
Virus Diseases
Oxidation-Reduction
Cerebrospinal Fluid
Oxidative Stress
Cell Death
Apoptosis
Cytokines
Lipids
Membranes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Perturbation of Sphingolipid Metabolism and Ceramide Production in HIV-Dementia. / Haughey, Norman; Cutler, Roy G.; Tamara, Anita; McArthur, Justin Charles; Vargas, Diana L.; Pardo-Villamizar, Carlos A; Turchan, Jadwiga; Nath, Avindra; Mattson, Mark P.

In: Annals of Neurology, Vol. 55, No. 2, 02.2004, p. 257-267.

Research output: Contribution to journalArticle

Haughey, Norman ; Cutler, Roy G. ; Tamara, Anita ; McArthur, Justin Charles ; Vargas, Diana L. ; Pardo-Villamizar, Carlos A ; Turchan, Jadwiga ; Nath, Avindra ; Mattson, Mark P. / Perturbation of Sphingolipid Metabolism and Ceramide Production in HIV-Dementia. In: Annals of Neurology. 2004 ; Vol. 55, No. 2. pp. 257-267.
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