title: The γ-secretase inhibitor DAPT increases the levels of gangliosides at neuritic terminals of differentiating PC12 cells.
abstract: Mutations in presenilins are the major cause of early onset familial Alzheimer disease. It has recently been argued that clinical presenilin mutations work as loss-of-function but not toxic gain-of-function. To investigate whether presenilins are involved in the regulation of the distribution of neuronal membrane lipids, we treated neuronally differentiated PC12 cells with DAPT, an inhibitor of presenilin-dependent γ-secretase, and performed lipid analyses of neuritic terminals, which is an initial site of Aβ deposition in brains, using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) in combination with multiple reaction monitoring (MRM). With DAPT treatment, levels of sphingomyelin, phosphatidylcholine, and cholesterol remained unchanged. However, DAPT treatment increased the ganglioside levels in PC12 neuritic terminals. Together with a previous finding that accumulation of gangliosides at neuritic terminals facilitates Aβ assembly and deposition, the present data suggest that the loss-of-function of presenilins, i.e., a decrease in γ-secretase activity, has an impact on neuronal membrane architecture in a way that eventually exacerbates Alzheimer pathology.
authors.affiliation: Department of Drug Discovery, Center for Development of Advanced Medicine for Dementia, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oikawa
authors.forename: Miho
authors.initials: M
authors.lastname: Goto
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D002454:Cell Differentiation; D002784:Cholesterol / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D005732:Gangliosides / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D010713:Phosphatidylcholines / Q000378:metabolism; D051381:Rats; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004151:Dipeptides; D005732:Gangliosides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases