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Published on: June 8, 2017
Apoptosis in experimental cerebral malaria: spatial profile of cleaved caspase-3 and ultrastructural alterations in
P Lackner1, C Burger, K Pfaller
1Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. peter.lackner@i-med.ac.at
Abstract:
Cerebral malaria (CM) is associated with high mortality and morbidity as a certain percentage of survivors suffers from persistent neurological sequelae. The mechanisms leading to death and functional impairments are yet not fully understood. This study investigated biochemical and morphological markers of apoptosis in the brains of mice infected with Plasmodium berghei ANKA. Cleaved caspase-3 was detected in the brains of animals with clinical signs of CM and immunoreactivity directly correlated with the clinical severity of the disease. Caudal parts of the brain showed more intense immunoreactivity for cleaved caspase-3. Double-labelling experiments revealed processing of caspase-3 primarily in neurons and oligodendrocytes. These cells also exhibited apoptotic-like morphological profiles in ultrastructural analysis. Further, cleavage of caspase-3 was found in endothelial cells. In contrast to neurons and oligodendrocytes, apoptosis of endothelial cells already occurred in early stages of the disease. Our results are the first to demonstrate processing of caspase-3 in different central nervous system cells of animals with CM. Apoptosis of endothelial cells may represent a critical issue for the development of the disease in the mouse model. Neurological signs and symptoms might be attributable, at least in part, to apoptotic degeneration of neurons and glia in advanced stages of murine CM.
Insights
Cerebral malaria (CM) involves brain cell apoptosis, particularly in neurons and oligodendrocytes. Endothelial cell apoptosis in early stages may drive disease progression in this mouse model.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Cerebral malaria (CM) presents significant mortality and neurological deficits.
- The underlying mechanisms of CM-induced brain damage remain unclear.
Purpose of the Study:
- To investigate apoptosis markers in the brains of mice infected with Plasmodium berghei ANKA.
- To correlate apoptosis with disease severity and identify affected cell types.
Main Methods:
- Detection of cleaved caspase-3 (apoptosis marker) via immunohistochemistry.
- Double-labelling to identify cell types undergoing apoptosis.
- Ultrastructural analysis for morphological evidence of apoptosis.
Main Results:
- Cleaved caspase-3 immunoreactivity correlated with CM clinical severity.
- Apoptosis was observed in neurons, oligodendrocytes, and endothelial cells.
- Endothelial cell apoptosis occurred earlier in the disease course than neuronal/glial apoptosis.
Conclusions:
- This study demonstrates caspase-3 processing in diverse CNS cells during murine CM.
- Endothelial cell apoptosis is a critical factor in CM pathogenesis.
- Neurological sequelae may result from neuronal and glial apoptosis in later disease stages.
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