ACAT as a drug target for Alzheimer's disease.
Accumulation of beta-amyloid peptide (Abeta) in the brain regions responsible for memory and cognitive functions is a neuropathological hallmark of Alzheimer's disease. Cholesterol may be involved in many aspects of Abeta metabolism. It affects generation, aggregation and clearance of Abeta in the brain. Not only the amount but also the distribution of cholesterol within cells appears to modulate Abeta biogenesis. ACAT is an enzyme that regulates subcellular cholesterol distribution by converting membrane cholesterol to cholesteryl esters for storage and transport. We have used various cell- and animal based models to show that inhibition of ACAT strongly reduces Abeta generation and protects from amyloid pathology. Here, we discuss data supporting ACAT inhibition as a strategy to treat Alzheimer's disease.
Huttunen
Henri J
HJ
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass. 02129, USA.
Kovacs
Dora M
DM
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1