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P4‐210: Effects of mild cholesterol depletion on APP processing and gamma‐secretase
Author(s) -
Guardia-Laguarta Cristina,
Coma Mireia,
Clarimon Jordi,
Sereno Lidia,
Agullo Jose Manuel,
Molina Laura,
Blesa Rafael,
Gomez-Isla Teresa,
Lleo Alberto
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.2278
Subject(s) - western blot , cholesterol , lipid raft , förster resonance energy transfer , lovastatin , chemistry , amyloid precursor protein , presenilin , blot , amyloid precursor protein secretase , amyloid beta , microbiology and biotechnology , biochemistry , biology , medicine , alzheimer's disease , fluorescence , gene , physics , disease , quantum mechanics , peptide
containing cerebrosides or gangliosides significantly increased -secretase activity over a phosphatidylcholine-only baseline, whereas the addition of phosphatidylinositol significantly decreased activity. Addition of soluble cholesterol in the presence of phospholipids differentially increased the cleavage of APP-, APLP1and Notch-like substrates in a dose-dependent manner. Reconstitution of -secretase in complex lipid mixtures revealed that a lipid raft-like composition supported the highest level of activity compared to other membrane compositions, and reconstitution in a brain lipid extract yielded much higher activity than in liver or heart extracts. Conclusions: Taken together, these results demonstrate that membrane lipid composition is a direct and potent modulator of -secretase and that cholesterol, in particular, plays a major regulatory role.