| Publication Abstract Display | | Type: Published Manuscript | | Title: Caspase cascades in Human Immunodeficiency Virus-associated neurodegeneration. | | Authors: Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D'Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA | | Contact: Department of Neurology, University of Washington, Seattle, Washington 98195, USA. gagarden@u.washington.edu | | Year: 2002 | | Publication: The Journal of Neuroscience : the official journal of the Society for Neuroscience | | Volume: 22 Issue: 10 Pages: 4015-24 | | Abstract:Many patients infected with human immunodeficiency virus-1 (HIV-1) develop a syndrome of neurologic deterioration known as HIV-associated dementia (HAD). Neurons are not productively infected by HIV-1; thus, the mechanism of HIV-induced neuronal injury remains incompletely understood. Several investigators have observed evidence of neuronal injury, including dendritic degeneration, and apoptosis in CNS tissue from patients with HAD. Caspase enzymes, proteases associated with the process of apoptosis, are synthesized as inactive proenzymes and are activated in a proteolytic cascade after exposure to apoptotic signals. Here we demonstrate that HAD is associated with active caspase-3-like immunoreactivity that is localized to the soma and dendrites of neurons in affected regions of the human brain. Additionally, the cascade of caspase activation was studied using an in vitro model of HIV-induced neuronal apoptosis. Increased caspase-3 proteolytic activity and mitochondrial release of cytochrome c were observed in cerebrocortical cultures exposed to the HIV coat protein gp120. Specific inhibitors of both the Fas/tumor necrosis factor-alpha/death receptor pathway and the mitochondrial caspase pathway prevented gp120-induced neuronal apoptosis. Caspase inhibition also prevented the dendrite degeneration observed in vivo in transgenic mice with CNS expression of HIV/gp120. These findings suggest that pharmacologic interventions aimed at the caspase enzyme pathways may be beneficial for the prevention or treatment of HAD. | | Keywords: AIDS Dementia Complex, Adult, Animals, Antigens, CD95, Apoptosis, Astrocytes, Brain, Caspase 1, Caspases, Cells, Cultured, Cytochrome c Group, Dendrites, Enzyme Activation, Enzyme Inhibitors, HIV Envelope Protein gp120, Humans, Mice, Mice, Transgenic, Microglia, Middle Aged, Neurons, Prospective Studies, Research Support, Non-U.S. Gov''t, Research Support, U.S. Gov''t, P.H.S., Tumor Necrosis Factor-alpha |
return to publications listing
|