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- W2895965462 abstract "Abnormal cholesterol metabolism is suspected as one of the factors contributing to Alzheimer disease (AD) pathogenesis. We and others have previously shown that γ-secretase dysfunction, which appears to be a main consequence caused by clinical presenilin mutations relevant to familial AD, increases cholesterol level in non-neuronal cells [1, 2]. Additionally, we proposed that increase of one of the γ-secretase substrates, amyloid precursor protein C-terminal fragments (APP-CTFs), is a possible mediator of the cholesterol increase [2]. In this study, we examined the involvement of APP-CTFs in the metabolism of cholesterol and lipid droplets [3] in neuronally differentiated SH-SY5Y (nSY5Y) cells and in mouse embryonic fibroblasts lacking APP expression (MEFs-APPKO). nSY5Y cells differentiated by retinoic acid or MEFs-wild type (MEFs-WT) or MEFs-APPKO were treated with a γ-secretase inhibitor, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). To suppress APP-CTF accumulation in nSY5Y cells upon DAPT treatment, cells were co-treated with inhibitors of α-secretase or β-secretase. Levels of lipid droplets and cholesterol were measured by oil red-O staining and enzymatic assay, respectively. γ-Secretase inhibition in nSY5Y cells by DAPT significantly increased levels of lipid droplet and cholesterol and affected the expression profile of the proteins involved in cholesterol metabolism, such as ABCA1, NPC1, sterol regulatory element-binding protein 2, and LDLR. Suppression of the DAPT-induced APP-CTFs accumulation completely rescued lipid droplet accumulation; however, cholesterol accumulation and abnormal expression profile of the proteins were not rescued by suppression of the APP-CTFs accumulation. Additionally, γ-secretase inhibition induced lipid droplet accumulation only in MEFs-WT but not in MEFs-APPKO in contrast to cholesterol accumulation, which was detected in both of them upon DAPT treatment. These results indicate that γ-secretase inhibition has complex effects on cellular lipid metabolism in neuronal and non-neuronal cells, partly involving accumulated APP-CTFs. References: 1) Grimm MO, et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nat Cell Biol. 2005;7(11):1118-1123. 2) Tamboli IY, et al. Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis. J Neurosci. 2008;28(46):12097-12106. 3) Area-Gomez E, et al. Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 2012;31(21):4106-4123." @default.
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- W2895965462 date "2018-07-01" @default.
- W2895965462 modified "2023-10-16" @default.
- W2895965462 title "P3‐151: GAMMA‐SECRETASE INHIBITION INDUCES LIPID DROPLET ACCUMULATION VIA APP‐CTF ACCUMULATION" @default.
- W2895965462 doi "https://doi.org/10.1016/j.jalz.2018.06.1509" @default.
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