title: Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease?
abstract: There is mounting evidence linking Abeta42 generation in Alzheimer's disease (AD) with sphingomyelin catabolism. Using microarray technology to study 17 brain regions from subjects with varying severity of AD and dementia we detected multiple gene expression abnormalities of the key enzymes that control sphingolipid metabolism. These changes were correlated with the progression of clinical dementia. The upregulation of gene expression of the enzymes controlling synthesis de novo of Cer and the downregulation of the enzymes involved in glycosphingolipid synthesis was evident as early in disease progression as in mild dementia. Together these changes suggest a shift in sphingolipid metabolism towards accumulation of Cer, depletion of glycosphingolipids and the reduction of synthesis of the anti-apoptosis signaling lipid-sphingosine 1-phosphate as a function of disease progression. This disrupted balance within the sphingolipid metabolism may trigger signaling events promoting neurodegeneration across cortical regions. This potential mechanism may provide a link between lipid metabolism disturbance and AD.
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6575, USA. pavel.katsel@mssm.edu
authors.forename: Pavel
authors.initials: P
authors.lastname: Katsel
authors.forename: Celeste
authors.initials: C
authors.lastname: Li
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002518:Ceramides / Q000378:metabolism*; D003704:Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D006028:Glycosphingolipids / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008297:Male; D016501:Neurites / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D058225:Plaque, Amyloid / Q000473:pathology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D013107:Sphingolipids / Q000235:genetics* / Q000378:metabolism*; D013109:Sphingomyelins / Q000096:biosynthesis; D013110:Sphingosine / Q000096:biosynthesis; D016875:tau Proteins / Q000378:metabolism
chemical_list: D002518:Ceramides; D006028:Glycosphingolipids; D013107:Sphingolipids; D013109:Sphingomyelins; D016875:tau Proteins; D012313:RNA; D013110:Sphingosine