Role of acyl-coenzyme a: cholesterol acyltransferase activity in the processing of the amyloid precursor protein.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory deficit, cognitive impairment, and personality changes accompanied by specific structural abnormalities in the brain. Deposition of amyloid-beta (Abeta) peptide into senile plaques is a consistent feature of the brains of patients affected by AD. Studies with both animal and cellular models of AD have shown that cholesterol homeostasis and distribution regulate Abeta generation. We have provided genetic, biochemical, and metabolic evidence that implicates intracellular cholesterol distribution, rather than total cholesterol levels, in the regulation of Abeta generation. This minireview focuses on the role of acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) in Abeta generation. In genetically mutant cell lines that overproduce cholesterol but cannot synthesize cholesteryl esters (CEs) because of deficient ACAT activity, Abeta production is almost completely inhibited. Acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) inhibitors, currently being developed for the treatment and prevention of atherosclerosis, reduce CE levels and Abeta generation by up to 50% in cell culture models of AD. Future mechanistic and transgenic animal studies are needed to evaluate the potential use of ACAT inhibitors in the therapeutic treatment or prevention of AD.
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit/NIND, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Luigi
L
Puglielli
Blake C
BC
Ellis
Laura A MacKenzie
LA
Ingano
Dora M
DM
Kovacs
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000214:Acyl Coenzyme A; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D002784:Cholesterol; D002785:Sterol O-Acyltransferase