Mild cholesterol depletion reduces amyloid-beta production by impairing APP trafficking to the cell surface.
It has been suggested that cellular cholesterol levels can modulate the metabolism of the amyloid precursor protein (APP) but the underlying mechanism remains controversial. In the current study, we investigate in detail the relationship between cholesterol reduction, APP processing and gamma-secretase function in cell culture studies. We found that mild membrane cholesterol reduction led to a decrease in Abeta(40) and Abeta(42) in different cell types. We did not detect changes in APP intracellular domain or Notch intracellular domain generation. Western blot analyses showed a cholesterol-dependent decrease in the APP C-terminal fragments and cell surface APP. Finally, we applied a fluorescence resonance energy transfer (FRET)-based technique to study APP-Presenilin 1 (PS1) interactions and lipid rafts in intact cells. Our data indicate that cholesterol depletion reduces association of APP into lipid rafts and disrupts APP-PS1 interaction. Taken together, our results suggest that mild membrane cholesterol reduction impacts the cleavage of APP upstream of gamma-secretase and appears to be mediated by changes in APP trafficking and partitioning into lipid rafts.
Guardia-Laguarta
Cristina
C
Alzheimer Laboratory, Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
Coma
Mireia
M
Pera
Marta
M
Clarimón
Jordi
J
Sereno
Lidia
L
Agulló
José M
JM
Molina-Porcel
Laura
L
Gallardo
Eduard
E
Deng
Amy
A
Berezovska
Oksana
O
Hyman
Bradley T
BT
Blesa
Rafael
R
Gómez-Isla
Teresa
T
Lleó
Alberto
A
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000172:deficiency*; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases