: Astrocytes participate in maintenance of brain homeostasis and disease pathogenesis. Reactive astrogliosis is associated with neural injury in a wide range of neurodegenerative diseases, including HIV-1 -associated dementia (HAD). We hypothesize that activation of astrocytes may transform these normally supportive cells into neurotoxic immune effectors. Interleukin-I (IL-1) beta is elevated in HAD and is known to activate astrocytes, thus, we have chosen it as a prototypical immune activator. RT-PCR, ELISA and Immunocytochemistry analyses of IL-1 beta-activated astrocytes showed an upregulation of Fas ligand (FasL), a death protein. Elevated levels of FasL were observed in cerebrospinal fluid of HAD patients. Preliminary data showed that culture supernatants from IL-1 beta-activated astrocytes induced injury in rat and human neurons in cell-free and co-culture systems. Activated astrocytes led to caspase activation in human neurons. These findings lead us to believe that expression of FasL by activated astrocytes represents a novel pathway for neuronal injury in HAD. In order to explore this hypothesis, a series of cellular, molecular, pharmacological and electrophysiological techniques will be utilized to address the following questions: 1) What role does FasL play in astrocyte-mediated neuronal injury? 2) What is the mechanism for FasL-induced neurotoxicity? And 3) How is FasL expression regulated in activated astrocytes? We believe that answers to these questions will be important in understanding the mechanism of HAD and other neurodegenerative diseases and may provide novel approaches for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043113-04
Application #
6894776
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Wong, May
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$209,475
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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