Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide.
The pathogenic event common to all forms of Alzheimer's disease is the abnormal accumulation of the amyloid beta-peptide (Abeta). Here we provide strong evidence that intracellular cholesterol compartmentation modulates the generation of Abeta. Using genetic, biochemical and metabolic approaches, we found that cholesteryl-ester levels are directly correlated with Abeta production. Acyl-coenzyme A:cholesterol acyltransferase (ACAT), the enzyme that catalyses the formation of cholesteryl esters, modulates the generation of Abeta through the tight control of the equilibrium between free cholesterol and cholesteryl esters. We also show that pharmacological inhibitors of ACAT, developed for the treatment of atherosclerosis, are potent modulators of Abeta generation, indicating their potential for use in the treatment of Alzheimer's disease.
Puglielli
L
L
Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Building 114, 16th Street, Charlestown, Massachusetts 02129-4404, USA.
Konopka
G
G
Pack-Chung
E
E
Ingano
L A
LA
Berezovska
O
O
Hyman
B T
BT
Chang
T Y
TY
Tanzi
R E
RE
Kovacs
D M
DM
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015415:Biomarkers; D002458:Cell Fractionation; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D053764:Presenilin-1; D011725:Pyridines / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011725:Pyridines; C413604:nicastrin protein; C087132:CP 113818; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse