Carboxy-terminal fragment of amyloid precursor protein mediates lipid droplet accumulation upon γ-secretase inhibition

• Verfasst von: Oikawa, Naoto [VerfasserIn]
• Verfasst von: Fabiano, Marietta [VerfasserIn]
• Verfasst von: Müller, Ulrike C. [VerfasserIn]
• Verfasst von: Walter, Jochen [VerfasserIn]
• Titel: Carboxy-terminal fragment of amyloid precursor protein mediates lipid droplet accumulation upon γ-secretase inhibition
• Verf.angabe: Naoto Oikawa, Marietta Fabiano, Ulrike C. Müller, Jochen Walter
• E-Jahr: 2021
• Jahr: 17 July 2021
• Umfang: 6 S.
• Teil: volume:570
• Teil: year:2021
• Teil: pages:137-142
• Teil: extent:6
• Fussnoten: Gesehen am 29.09.2021
• Titel Quelle: Enthalten in: Biochemical and biophysical research communications
• Ort Quelle: Orlando, Fla. : Academic Press, 1959
• Jahr Quelle: 2021
• Band/Heft Quelle: 570(2021), Seite 137-142
• ISSN Quelle: 1090-2104
• DOI: doi:10.1016/j.bbrc.2021.07.021
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Alzheimer disease
• Sach-SW: C-terminal fragment of amyloid precursor protein
• Sach-SW: Cholesterol
• Sach-SW: Lipid droplet
• Sach-SW: γ-Secretase
• K10plus-PPN: 1772051993

Abstract

γ-Secretase is a protease catalysing the proteolysis of type-I membrane proteins usually after precedent ectodomain shedding of the respective protein substrates. Since proteolysis of membrane proteins is involved in fundamental cellular signaling pathways, dysfunction of γ-secretase can have significant impact on cellular metabolism and differentiation. Here, we examined the role of γ-secretase in cellular lipid metabolism using neuronally differentiated human SH-SY5Y cells. The pharmacological inhibition of γ-secretase induced lipid droplet (LD) accumulation. The LD accumulation was significantly attenuated by preventing the accumulation of C-terminal fragment of the amyloid precursor protein (APP-CTF), which is a direct substrate of γ-secretase. Additionally, LD accumulation upon γ-secretase inhibition was not induced in APP-knock out (APP-KO) mouse embryonic fibroblasts (MEFs), suggesting significant involvement of APP-CTF accumulation in LD accumulation upon γ-secretase inhibition. On the other hand, γ-secretase inhibition-dependent cholesterol accumulation was not attenuated by inhibition of APP-CTF accumulation in the differentiated SH-SY5Y cells nor in APP-KO MEFs. These results suggest that γ-secretase inhibition can induce accumulation of LD and cholesterol differentially via APP-CTF accumulation.