ACAT inhibition and amyloid beta reduction.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder. Accumulation and deposition of the beta-amyloid (Abeta) peptide generated from its larger amyloid precursor protein (APP) is one of the pathophysiological hallmarks of AD. Intracellular cholesterol was shown to regulate Abeta production. Recent genetic and biochemical studies indicate that not only the amount, but also the distribution of intracellular cholesterol is critical to regulate Abeta generation. Acyl-coenzyme A: cholesterol acyl-transferase (ACAT) is a family of enzymes that regulates the cellular distribution of cholesterol by converting membrane cholesterol into hydrophobic cholesteryl esters for cholesterol storage and transport. Using pharmacological inhibitors and transgenic animal models, we and others have identified ACAT1 as a potential therapeutic target to lower Abeta generation and accumulation. Here we discuss data focusing on ACAT inhibition as an effective strategy for the prevention and treatment of AD.
Bhattacharyya
Raja
R
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Kovacs
Dora M
DM
D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D055503:Protein Multimerization / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects
D016564:Amyloid beta-Protein Precursor; D002491:Central Nervous System Agents; D000101:Acetyl-CoA C-Acetyltransferase
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