Caspase cascades in human immunodeficiency virus-associated neurodegeneration.
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.
Garden
Gwenn A
GA
Department of Neurology, University of Washington, Seattle, Washington 98195, USA. gagarden@u.washington.edu
Budd
Samantha L
SL
Tsai
Elena
E
Hanson
Lisa
L
Kaul
Marcus
M
D'Emilia
Danielle M
DM
Friedlander
Robert M
RM
Yuan
Junying
J
Masliah
Eliezer
E
Lipton
Stuart A
SA
D015526:AIDS Dementia Complex / Q000201:enzymology*; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000473:pathology; D020170:Caspase 1 / Q000235:genetics; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D003712:Dendrites / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000633:toxicity; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D019014:fas Receptor / Q000187:drug effects
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1