Journal
GLIA
Volume 56, Issue 4, Pages 449-456Publisher
WILEY-BLACKWELL
DOI: 10.1002/glia.20626
Keywords
ceramide; presenilin 1; Alzheimer; apoptosis; glia; lass genes
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Funding
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS046835] Funding Source: NIH RePORTER
- NINDS NIH HHS [R01NS046835] Funding Source: Medline
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The pro-apoptotic sphingolipid ceramide plays an emergent role in the etiology of Alzheimer's disease (AD), although its function for neurodegeneration is not known. We determined the concentration and composition of ceramide in hippocampal tissue from newborn presenilin 1 (PS1) knockin (PS1M146V) mice, a mouse model for early-onset familial AD. We found that PSI tissue contains 3.1 (+/- 0.5)-fold more total ceramide than wild-type tissue. In particular, the proportion of C20 and C24 ceramide is increased by 4.0- or 8.5-fold, respectively. The ceramide elevation in PS1 brain is consistent with a 3.7 (+/- 0.5)-fold increase of the protein level of the neurotrophin receptor p75NTR, which has been suggested to stimulate the hydrolysis of sphingomyelin to generate ceramide. The predominance of C20 and C24 ceramide is concurrent with the elevated gene expression of lass 2 and lass 4, two isoforms of ceramide synthase that generate dihydroceramide with long-chain fatty acid. Our study indicates that primary cultured astrocytes but not neurons from PS1 mice undergo apoptosis when incubated with C20 ceramide. In contrast, wild-type astrocytes remain unaffected. The sensitivity of PS1 astrocytes is most likely due to the 9.5 (+/- 0.4)-fold elevated expression of PAR-4 (prostate apoptosis response-4), a protein that inhibits atypical PKC xi/lambda, in the presence of ceramide. Our results suggest that astroglial death due to ceramide/PAR-4-induced apoptosis may critically contribute to the etiology of AD. (c) 2008 Wiley-Liss, Inc.
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