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Review
. 2009 Mar 15;278(1-2):5-15.
doi: 10.1016/j.jns.2008.12.010. Epub 2009 Jan 14.

Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death

Arundhati Jana  1 , Edward L Hogan, Kalipada Pahan
Affiliations
Review

Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death

Arundhati Jana et al. J Neurol Sci. .

Abstract

Neurodegenerative disorders are marked by extensive neuronal apoptosis and gliosis. Although several apoptosis-inducing agents have been described, understanding of the regulatory mechanisms underlying modes of cell death is incomplete. A major breakthrough in delineation of the mechanism of cell death came from elucidation of the sphingomyelin (SM)-ceramide pathway that has received worldwide attention in recent years. The SM pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and on downstream _targets. Sphingomyelin, a plasma membrane constituent, is abundant in mammalian nervous system, and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Neutral sphingomyelinase (NSMase) is a key enzyme in the regulated activation of the SM cycle and is particularly sensitive to oxidative stress. In a context of increasing clarification of the mechanisms of neurodegeneration, we thought that it would be useful to review details of recent findings that we and others have made concerning different pro-apoptotic neurotoxins including proinflammatory cytokines, hypoxia-induced SM hydrolysis and ceramide production that induce cell death in human primary neurons and primary oligodendrocytes: redox sensitive events. What has and is emerging is a vista of therapeutically important ceramide regulation affecting a variety of different neurodegenerative and neuroinflammatory disorders.

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Figures

Fig. 1
Fig. 1. Schematic representation of ceramide-induced various apoptotic pathways
Sphingomyelinases cleave sphingomyelin (represented as small circles around the membrane) to ceramide in response to different extracellular insults. Once ceramide is generated, different downstream _targets including death-associated protein kinase (DAPK), kinase suppressor of Ras (KSR), protein kinase C (PKC) ζ, Rac, inducible nitric oxide synthase (iNOS), ceramide-activated protein phosphatase (CAPP), and c-Jun N-terminal kinase (JNK) are activated and the release of cytochrome C is augmented. On the other hand, the anti-apoptotic Akt - Bcl2 pathway is down-regulated. All these events eventually lead to apoptosis.
Fig. 2
Fig. 2. Model showing the possible involvement of NSMase-ceramide pathway in neuronal apoptosis and cell death under different neurodegenerative conditions
Fibrillar Aβ1–42 peptides induce neuronal apoptosis through the NADPH oxidase-superoxide-hydrogen peroxide-NSMase-ceramide pathway. On the other hand, HIV-1 gp120 requires CXCR4 to activate the same apoptotic pathway in neurons.
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