title: GD3 accumulation in cell surface lipid rafts prior to mitochondrial targeting contributes to amyloid-β-induced apoptosis.
abstract: Neuronal apoptosis induced by amyloid β-peptide (Aβ) plays an important role in the pathophysiology of Alzheimer's disease (AD). However, the molecular mechanism underlying Aβ-induced apoptosis remains undetermined. The disialoganglioside GD3 involves ceramide-, Fas- and TNF-α-mediated apoptosis in lymphoid cells and hepatocytes. Although the implication of GD3 has been suggested, the precise role of GD3 in Aβ-induced apoptosis is still unclear. Here, we investigated the changes of GD3 metabolism and characterized the distribution and trafficking of GD3 during Aβ-induced apoptosis using human brain-derived TE671 cells. Extracellular Aβ-induced apoptosis in a mitochondrial-dependent manner. GD3 level was negligible in the basal condition. However, in response to extracellular Aβ, both the expression of GD3 synthase mRNA and the intracellular GD3 level were dramatically increased. Neosynthesized GD3 rapidly accumulated in cell surface lipid microdomains, and was then translocated to mitochondria to execute the apoptosis. Disruption of membrane lipid microdomains with methyl-β-cyclodextrin significantly prevented both GD3 accumulation in cell surface and Aβ-induced apoptosis. Our data suggest that rapidly accumulated GD3 in plasma membrane lipid microdomains prior to mitochondrial translocation is one of the key events in Aβ-induced apoptosis.
authors.affiliation: Department of Neurology, Dong-A University College of Medicine, Medical Science Research Center, Busan, Korea.
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Kim
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Cho
authors.forename: Hee-Soo
authors.initials: HS
authors.lastname: Shin
authors.forename: Hye-Ryen
authors.initials: HR
authors.lastname: Sung
authors.forename: Jin-Ran
authors.initials: JR
authors.lastname: Jung
authors.forename: Mei-Lian
authors.initials: ML
authors.lastname: Quan
authors.forename: Dong-Hong
authors.initials: DH
authors.lastname: Jiang
authors.forename: Hae-Rahn
authors.initials: HR
authors.lastname: Bae
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D005732:Gangliosides / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D005732:Gangliosides; D047392:beta-Cyclodextrins; C026226:ganglioside, GD3; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; C031215:betadex