Apoptosis in experimental cerebral malaria: spatial profile of cleaved caspase‐3 and ultrastructural alterations in different disease stages

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.

Cerebral Malaria Pathogenesis

“…Although other studies have suggested the importance of IFN, particularly IFN-␥, in murine CM, 19 only two very recent studies have documented neuronal apoptosis in murine CM. 20,21 Lovegrove and colleagues 4 confirm these findings of neuronal apoptosis in murine CM and also provide, through microarray analysis, a number of potential pathways by which neuronal apoptosis may occur. The study findings of Lovegrove and colleagues 4 nicely demonstrate the potential for microarray analysis to lead to significant new discoveries in murine CM pathogenesis.…”

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

“…Group H includes genes downregulated only in PbA(6) (n ϭ 65), group I includes genes downregulated only in PbK(6) (n ϭ 168), group J includes genes downregulated only in PbK(14) (n ϭ 81), group K includes genes downregulated in PbA(6) പ PbK(6) (n ϭ 22), group L includes genes downregulated in PbA(6) പ PbK(14) (n ϭ 11), group M includes genes downregulated in PbK(6) പ PbK(14) (n ϭ 10), and group N includes genes downregulated in all groups (n ϭ 9). Neutrophil cytosolic factor 1 Histocompatibility 2, Q region locus 10 Nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, zeta Histocompatibility 2, T region locus 9 P lysozyme structural Histocompatibility 2, T region locus 10 Peptidoglycan recognition protein 1 Histocompatibility 2, T region locus 22 Ring finger protein 125 Histocompatibility 2, T region locus 23 SAM domain and HD domain, 1 Histocompatibility 2, T region locus 24 Serine (or cysteine) peptidase inhibitor, clade A, member 3G IFN-␥-inducible protein 30 Serine (or cysteine) peptidase inhibitor, clade A, member 3N MHC A.CA/J(H-2K-F) class I antigen Serine (or cysteine) peptidase inhibitor, clade G, member 1 Proteasome (prosome, macropain) 28 subunit, alpha Serum amyloid A 3 Proteasome (prosome, macropain) 28 subunit, beta T-cell specific GTPase P. berghei infection, due in part to the green bias on oligonucleotide arrays. Moreover, since many of the genes found in these lists were not annotated, these were not explored further here.…”

“…Both pathways converge on caspase 3, which also is involved in the pathogenesis of FMCM (23,36,(45)(46)(47).…”

“…Significantly, these were much more strongly induced in PbA infection than in PbK infection. Apoptosis occurs in the brain during human and murine CM in endothelial cells (45,46,65), astrocytes (47), and neurons (23,53,65). Both the death receptor-mediated pathway and the a Vessels were separated from parenchymal cells (neurons and glia) in PbA-infected mouse brains as described previously (38).…”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…Apoptosis sequentially occurred in different cells. In murine models, apoptosis occurs in endothelial cells first, and is followed by neuronal and glia cells (Lackner, Burger et al 2007). P. falciparum-pRBCs increase the expression of ICAM-1 and CD36 (Collins, Read et al 1995;Tripathi, Sullivan et al 2006;Tripathi, Sha et al 2009) which strengthens sequestration, probably through NF-kappa B (Collins, Read et al 1995;Tripathi, Sullivan et al 2006;Tripathi, Sha et al 2009) and MAP Kinase activation (Yipp, Robbins et al 2003).…”