Commentary: “Ceramide and cholesterol: Possible connections between normal aging of the brain and Alzheimer's disease. Just hypotheses or molecular pathways to be identified?” By Claudio Costantini, Rekha M.K. Kolasani, and Luigi Puglielli

The middleman or the missing link: the role of cer- amide in Alzheimer's disease—Ceramide, a lipid precur- sor in the production of a crucial component of mem- branes called sphingomyelin, also plays a key role in the regulation of a multitude of cellular processes. By serv- ing as a potent second messenger, ceramide is implicated in the regulation of proliferation, survival, and differen- tiation of the cell as well as inflammatory activity and cholesterol metabolism to name but a few of ceramide's key functions. In an eloquently presented review by Costantin ie ta l(1) ,th epivota lrol eo fceramid ei nme- diating the relationship between lipid composition and the regulation and production of the amyloid- peptide, in addition to its link to oxidative stress, senescence, and cell death of neurons in Alzheimer disease (AD) is dis- cussed. As highlighted, the promiscuity of ceramide would allow it to be actively involved in most, if not all, of the pathogenic events occurring in AD. Of central importance, given the age-related increase in AD, studies have found that ceramide is increased during aging. Moreover, recent data described in the current review, suggest that ceramide can increase amy- loid- protein precursor (APP) processing and amy- loid- generation by stabilizing BACE1, a key protease mediating the liberation of amyloid- from its precursor. These studies, together with additional evidence regard- ing cholesterol homeostasis and distribution in neurons, as the authors suggest, could provide the missing link between aging and AD. However, an alternative expla- nation for these findings, based on the stress-response role of the ceramide-sphingomyelin (SM) pathway,