GD3 accumulation in cell surface lipid rafts prior to mitochondrial targeting contributes to amyloid-β-induced apoptosis.
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.
Kim
Jong-Kook
JK
Department of Neurology, Dong-A University College of Medicine, Medical Science Research Center, Busan, Korea.
Kim
Sang-Ho
SH
Cho
Hee-Young
HY
Shin
Hee-Soo
HS
Sung
Hye-Ryen
HR
Jung
Jin-Ran
JR
Quan
Mei-Lian
ML
Jiang
Dong-Hong
DH
Bae
Hae-Rahn
HR
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
D016229:Amyloid beta-Peptides; D005732:Gangliosides; D047392:beta-Cyclodextrins; C026226:ganglioside, GD3; D012799:Sialyltransferases; C043662:alpha-N-acetylneuraminate alpha-2,8-sialyltransferase; C031215:betadex