title: PS dependent APP cleavage regulates glucosylceramide synthase and is affected in Alzheimer's disease.
abstract: BACKGROUND
  Gangliosides were found to be associated with Alzheimer's disease (AD). Here we addressed a potential function of γ-secretase (presenilin) dependent cleavage of the amyloid-precursor-protein (APP) in the regulation of ganglioside de novo synthesis.
  
  
  METHODS
  To identify a potential role of γ-secretase and APP in ganglioside de novo synthesis we used presenilin (PS) deficient and APP deficient cells and mouse brains, mutated PS as well as transgenic mice and AD post mortem brains. Changes in glucosylceramide synthase (GCS) activity were identified by incorporation of radiolabeled UDP-glucose in glucosylceramide, changes in gene expression via real-time PCR and Western blot analysis. Alterations in ganglioside levels were determined by thin layer chromatography and mass spectrometry.
  
  
  RESULTS
  We found that PS and APP deficiency, in vitro and in vivo, resulted in increased GCS gene expression, elevated enzyme activity and thus increased glucosylceramide and total ganglioside level. Using a specific γ-secretase inhibitor revealed that PS proteolytic activity alters ganglioside homeostasis. By the use of mutated PS causing early onset AD in cell culture and transgenic mice we found that GCS is increased in AD, further substantiated by the use of AD post mortem brains, suffering from sporadic AD.
  
  
  CONCLUSIONS
  APP processing regulates ganglioside de novo synthesis and is affected in AD.
authors: Experimental Neurology, Saarland University, Homburg/Saar, Germany.
authors: Marcus O W
authors: MO
authors: Grimm
authors: Benjamin
authors: B
authors: Hundsdörfer
authors: Sven
authors: S
authors: Grösgen
authors: Janine
authors: J
authors: Mett
authors: Valerie C
authors: VC
authors: Zimmer
authors: Christoph P
authors: CP
authors: Stahlmann
authors: Viola J
authors: VJ
authors: Haupenthal
authors: Tatjana L
authors: TL
authors: Rothhaar
authors: Johannes
authors: J
authors: Lehmann
authors: Andreas
authors: A
authors: Pätzold
authors: Eva G
authors: EG
authors: Zinser
authors: Heikki
authors: H
authors: Tanila
authors: Jie
authors: J
authors: Shen
authors: Ulrike
authors: U
authors: Müller
authors: Heike S
authors: HS
authors: Grimm
authors: Tobias
authors: T
authors: Hartmann
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D005732:Gangliosides / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053763:Presenilins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D005732:Gangliosides; D053763:Presenilins; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D053829:Amyloid Precursor Protein Secretases