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J. Biol. Chem., Vol. 278, Issue 22, 19777-19783, May 30, 2003

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Ceramide Stabilizes -Site Amyloid Precursor Protein-cleaving Enzyme 1 and Promotes Amyloid -Peptide Biogenesis^*

Luigi Puglielli   ¶, Blake C. Ellis  , Aleister J. Saunders || ** and Dora M. Kovacs  

From the Neurobiology of Disease Laboratory and ^||Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

The lipid second messenger ceramide regulates several biochemical events that occur during aging. In addition, its level is highly elevated in the amyloid-burdened brains of Alzheimer's disease patients. Here, we analyzed the impact of aberrant ceramide levels on amyloid -peptide (A) generation by using a cell-permeable analog of ceramide, C6-ceramide, and several biochemical inhibitors of the sphingomyelin/glycosphingolipid biosynthetic pathway. We found that C6-ceramide increased the biogenesis of A by affecting -but not -cleavage of the amyloid precursor protein. Similarly to C6-ceramide, increased levels of endogenous ceramide induced by neutral sphingomyelinase treatment also promoted the biogenesis of A. Conversely, fumonisin B1, which inhibits the biosynthesis of endogenous ceramide, reduced A production. Exogenous C6-ceramide restored both intracellular ceramide levels and A generation in fumonisin B1-treated cells. These events were specific for amyloid precursor protein and were not associated with apoptotic cell death. Pulse-chase and time-course degradation experiments showed that ceramide post-translationally stabilizes the -secretase BACE1. Taken together, these data indicate that the lipid second messenger ceramide, which is elevated in the brains of Alzheimer's disease patients, increases the half-life of BACE1 and thereby promotes A biogenesis.

Received for publication, January 15, 2003 , and in revised form, March 5, 2003.

^* This research was supported by grants from the Alzheimer's Association (to L. P.), the NINDS, National Institutes of Health (D. M. K.), and the American Health Assistance Foundation (to D. M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to the execution of the experiments described in this study.

^** Present address: Dept. of Bioscience and Biotechnology, Drexel University, Philadelphia, PA 19104.

^¶ To whom correspondence may be addressed: Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, CAGN, Massachusetts General Hospital, Harvard Medical School, 114 16th St., Charlestown, MA 02129. Tel.: 617-724-1505; Fax: 617-724-1823; E-mail: pugliell{at}helix.mgh.harvard.edu. To whom correspondence may also be addressed: Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, CAGN, Massachusetts General Hospital, Harvard Medical School, 114 16th St., Charlestown, MA 02129. Tel.: 617-726-3668; Fax: 617-724-1823; E-mail: kovacs{at}helix.mgh.harvard.edu.

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