Long-chain ceramide is elevated in presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 astrocytes.

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) knock-in (PS1M146V) mice, a mouse model for early-onset familial AD. We found that PS1 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 zeta/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.