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The Journal of Neuroscience, May 15, 2002, 22(10):4015-4024
Caspase Cascades in Human Immunodeficiency Virus-Associated
Neurodegeneration
Gwenn A.
Garden1, 2, 3,
Samantha L.
Budd2, 3,
Elena
Tsai3,
Lisa
Hanson1,
Marcus
Kaul2, 3,
Danielle M.
D'Emilia3,
Robert M.
Friedlander3,
Junying
Yuan4,
Eliezer
Masliah5, and
Stuart A.
Lipton2, 3, 5
1 Department of Neurology, University of Washington,
Seattle, Washington 98195, 2 Center for Neuroscience and
Aging, The Burnham Institute, La Jolla, California 92037, 3 Neuroapoptosis Laboratory and CNS Research Institute,
Department of Neurosurgery, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115, 4 Department
of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, and 5 Department of Neurosciences, University of
California, San Diego, La Jolla, California 92037
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- /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.
Key words:
apoptosis; caspase; dendrite degeneration; deconvolution
microscopy; HIV-associated dementia; tumor necrosis factor
Copyright © 2002 Society for Neuroscience 0270-6474/02/22104015-10$05.00/0
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