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Expression of caspase-3 in brains from paediatric patients with HIV-1 encephalitis
H J James1, L R Sharer, Q Zhang
1Department of Neurology (Child Neurology Division), The University of Rochester Medical Center, NY 14642, USA.
Insights
Neuronal apoptosis in pediatric HIV encephalitis involves caspase-3 upregulation, independent of Bax-Bcl-2, preceding DNA fragmentation in progressive encephalopathy.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Human Immunodeficiency Virus (HIV) type 1 encephalitis in children often leads to progressive encephalopathy.
- Neuronal apoptosis is a key feature, with prior studies showing a lack of Bax in TUNEL-positive neurons.
Purpose of the Study:
- To investigate the role of caspase-3 in neuronal apoptosis in pediatric HIV encephalitis.
- To determine if the Bax-Bcl-2 pathway is involved in this apoptotic process.
Main Methods:
- Immunocytochemical analysis of brain tissue from pediatric patients with HIV type 1 encephalitis.
- Detection of caspase-3 expression and its co-localization with TUNEL staining (DNA fragmentation marker).
Main Results:
- Neurones, macrophages, and microglia overexpressed caspase-3, a pro-apoptotic enzyme.
- Astrocytes did not show increased caspase-3 levels.
- Co-localization of caspase-3 and TUNEL staining in neurons was infrequent.
- Neuronal caspase-3 upregulation occurred independently of Bax-Bcl-2 dysregulation.
Conclusions:
- Neuronal apoptosis in pediatric HIV encephalitis utilizes a caspase-3-dependent pathway.
- This pathway appears independent of the Bax-Bcl-2 pathway.
- Caspase-3 upregulation likely precedes DNA fragmentation in affected neurons.
Abstract:
Apoptosis of neurones, macrophages, and microglia occurs in the brains of paediatric patients with human immunodeficiency virus (HIV) type 1 encephalitis, which is often associated with pre-mortem neurological disease (progressive encephalopathy). We have previously reported that TUNEL-positive neurones in brain tissue from paediatric patients with HIV type 1 encephalitis and progressive encephalopathy are strikingly devoid of the pro-apoptotic gene product Bax, in marked contrast to brain-resident macrophages and microglia. Using immunocytochemical methods, the present study demonstrate that neurones in patients with HIV type 1 encephalitis and progressive encephalopathy, as well as macrophages and microglia, but not astrocytes, overexpress caspase-3, a pro-apoptotic enzyme that is proteolytically activated downstream of Bax-Bcl-2 dysregulation. Co-localization of neuronal cytoplasmic caspase-3 and nuclear TUNEL staining, a marker for fragmented DNA, was also infrequently observed in brain tissue from patients with HIV type 1 encephalitis and progressive encephalopathy. These findings suggest that vulnerable neurones in brain tissue from patients with HIV virus type 1 encephalitis and progressive encephalopathy undergo apoptosis by a mechanism that involves upregulation of caspase-3 in a pathway that is independent of Bax-Bcl-2 dysregulation. Furthermore, caspase-3 upregulation in apoptotic neurones likely occurs prior to DNA fragmentation.