The γ-secretase inhibitor DAPT increases the levels of gangliosides at neuritic terminals of differentiating PC12 cells

• Published in: Neuroscience letters 2012-09, Vol.525 (1), p.49-53
• Main Authors: Oikawa, Naoto, Goto, Miho, Ikeda, Kazutaka, Taguchi, Ryo, Yanagisawa, Katsuhiko
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Amyloid beta-Peptides - biosynthesis; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid β-protein; Animals; Cell Differentiation; Cholesterol - metabolism; Dipeptides - pharmacology; Ganglioside; Gangliosides - metabolism; Lipidomics; Liquid chromatography/electrospray ionization tandem mass spectrometry; Neurites - drug effects; Neurites - metabolism; PC12 Cells; Phosphatidylcholines - metabolism; Rats; Sphingomyelins - metabolism; γ-Secretase
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2012.07.027

► The γ-secretase inhibitor DAPT perturbed Aβ production like clinical presenilin mutations. ► Lipidomics protocol for neuritic terminals of PC12 cells was established. ► The γ-secretase inhibitor DAPT increased the gangliosides at neuritic terminals. 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.