Calpastatin reduces calpain and caspase activation in methamphetamine-induced toxicity in human neuroblastoma SH-SY5Y cultured cells |
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Authors: | Wilasinee Suwanjang Pansiri Phansuwan-Pujito Piyarat Govitrapong Banthit Chetsawang |
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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. |
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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. |
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Keywords: | Aβ, amyloidβ-peptide AD, Alzheimer disease APP, β-amyloid precursor protein ESI, electrospray ionization GAβ, ganglioside-bound Aβ LC, liquid chromatography MRM, multiple reaction monitoring MS, mass spectrometry MS/MS, tandem mass spectrometry nanoESI, nanospray ESI NGF, nerve growth factor NT, neuritic terminal plasma membrane PS, presenilin UPLC, ultraperformance liquid chromatography |
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