Proceedings of the National Academy of Sciences - PNAS, 2007-02, Vol.104 (9), p.3438-3443
2007
Details
- Autor(en) / Beteiligte
- Titel
- HIV-tat induces formation of an LRP-PSD-95- NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2007-02, Vol.104 (9), p.3438-3443
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2007
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- HIV infection of the central nervous system can result in neurologic dysfunction with devastating consequences in AIDS patients. NeuroAIDS is characterized by neuronal injury and loss, yet there is no evidence that HIV can infect neurons. Here we show that the HIV-encoded protein tat triggers formation of a macromolecular complex involving the low-density lipoprotein receptor-related protein (LRP), postsynaptic density protein-95 (PSD-95), N-methyl-D-aspartic acid (NMDA) receptors, and neuronal nitric oxide synthase (nNOS) at the neuronal plasma membrane, and that this complex leads to apoptosis in neurons negative as well as positive for NMDA receptors and also in astrocytes. Blockade of LRP-mediated tat uptake, NMDA receptor activation, or neuronal nitric oxide synthase significantly reduces ensuing neuronal apoptosis, suggesting that formation of this complex is an early step in tat toxicity. We also show that the inflammatory chemokine, CCL2, protects against tat toxicity and inhibits formation of the complex. These findings implicate the complex in HIV-induced neuronal apoptosis and suggest therapeutic targets for intervention in the pathogenesis of NeuroAIDS.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.0611699104Titel-ID: cdi_pnas_primary_104_9_3438
- Format
- –
- Schlagworte
- Apoptosis, Apoptosis - drug effects, Apoptosis - physiology, Astrocytes, Astrocytes - physiology, Biological Sciences, Blotting, Western, Central nervous system, Chemokine CCL2 - metabolism, Chemokine CCL2 - pharmacology, Disks Large Homolog 4 Protein, Electrophoresis, Polyacrylamide Gel, Fetus, Gene Products, tat - genetics, Gene Products, tat - metabolism, Gene Products, tat - toxicity, HIV, HIV Infections - genetics, HIV Infections - metabolism, HIV-1 - genetics, Human immunodeficiency virus, Humans, In Situ Nick-End Labeling, Intracellular Signaling Peptides and Proteins - metabolism, LDL-Receptor Related Proteins - metabolism, Ligands, Membrane Proteins - metabolism, Microscopy, Confocal, Multiprotein Complexes - metabolism, Neurological disorders, Neurology, Neurons, Neurons - physiology, Neuroscience, Nitric Oxide Synthase Type I - metabolism, Oxides, Pixels, Proteins, Receptors, Receptors, N-Methyl-D-Aspartate - metabolism, Statistics, Nonparametric, tat Gene Products, Human Immunodeficiency Virus