Mild cholesterol depletion reduces amyloid-β production by impairing APP trafficking to the cell surface

• Published in: Journal of neurochemistry 2009-07, Vol.110 (1), p.220-230
• Main Authors: Guardia-Laguarta, Cristina, Coma, Mireia, Pera, Marta, Clarimón, Jordi, Sereno, Lidia, Agulló, José M, Molina-Porcel, Laura, Gallardo, Eduard, Deng, Amy, Berezovska, Oksana, Hyman, Bradley T, Blesa, Rafael, Gómez-Isla, Teresa, Lleó, Alberto
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Animals; Biological and medical sciences; Brain - metabolism; Cell Line; CHO Cells; cholesterol; Cholesterol - deficiency; Cricetinae; Cricetulus; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disorders of blood lipids. Hyperlipoproteinemia; Down-Regulation - physiology; FLIM; FRET; Humans; Medical sciences; Membrane Microdomains - metabolism; Metabolic diseases; Neurology; Neurons - metabolism; Peptide Fragments - metabolism; Plaque, Amyloid - metabolism; presenilin; Presenilin-1 - metabolism; Protein Structure, Tertiary - physiology; Protein Transport - physiology; rafts; statins; γ-secretase
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06126.x

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 γ-secretase function in cell culture studies. We found that mild membrane cholesterol reduction led to a decrease in Aβ₄₀ and Aβ₄₂ 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 γ-secretase and appears to be mediated by changes in APP trafficking and partitioning into lipid rafts.