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We determined the concentration and composition of ceramide in hippocampal tissue from newborn presenilin 1 (PS1) knock\u2010in (PS1M146V) mice, a mouse model for early\u2010onset familial AD. We found that PS1 tissue contains 3.1 (\u00b10.5)\u2010fold more total ceramide than wild\u2010type tissue. In particular, the proportion of C20 and C24 ceramide is increased by 4.0\u2010 or 8.5\u2010fold, respectively. The ceramide elevation in PS1 brain is consistent with a 3.7 (\u00b10.5)\u2010fold 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 <jats:italic>lass 2<\/jats:italic> and <jats:italic>lass 4<\/jats:italic>, two isoforms of ceramide synthase that generate dihydroceramide with long\u2010chain 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\u2010type astrocytes remain unaffected. The sensitivity of PS1 astrocytes is most likely due to the 9.5 (\u00b10.4)\u2010fold elevated expression of PAR\u20104 (prostate apoptosis response\u20104), a protein that inhibits atypical PKC\u03b6\/\u03bb in the presence of ceramide. Our results suggest that astroglial death due to ceramide\/PAR\u20104\u2010induced apoptosis may critically contribute to the etiology of AD. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.20626","type":"journal-article","created":{"date-parts":[[2008,1,18]],"date-time":"2008-01-18T20:16:29Z","timestamp":1200687389000},"page":"449-456","source":"Crossref","is-referenced-by-count":53,"title":["Long\u2010chain ceramide is elevated in presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 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