title: Elevation in sphingomyelin synthase activity is associated with increases in amyloid-beta peptide generation.
abstract: A pathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-beta peptide (Aβ) plaques in the brain. Aβ is derived from a sequential proteolysis of the transmenbrane amyloid precursor protein (APP), a process which is dependent on the distribution of lipids present in the plasma membrane. Sphingomyelin is a major membrane lipid, however its role in APP processing is unclear. Here, we assessed the expression of sphingomyelin synthase (SGMS1; the gene responsible for sphingomyelin synthesis) in human brain and found that it was significantly elevated in the hippocampus of AD brains, but not in the cerebellum. Secondly, we assessed the impact of altering SGMS activity on Aβ generation. Inhibition of SGMS activity significantly reduced the level of Aβ in a dose- and time dependent manner. The decrease in Aβ level occurred without changes in APP expression or cell viability. These results when put together indicate that SGMS activity impacts on APP processing to produce Aβ and it could be a contributing factor in Aβ pathology associated with AD.
authors: Neuroscience Research Australia, Sydney, New South Wales, Australia.
authors: Jen-Hsiang T
authors: JH
authors: Hsiao
authors: Yuhong
authors: Y
authors: Fu
authors: Andrew F
authors: AF
authors: Hill
authors: Glenda M
authors: GM
authors: Halliday
authors: Woojin Scott
authors: WS
authors: Kim
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D016466:CHO Cells; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009636:Norbornanes; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013107:Sphingolipids / Q000096:biosynthesis; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D001952:Bridged-Ring Compounds; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009636:Norbornanes; D013107:Sphingolipids; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups)
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