Cholesterol metabolism ADds up

Abstract

Reports by independent teams at Dartmouth College and Albert Einstein College of Medicine of Yeshiva University suggest that blocking production and transport of cholesteryl esters, the extracellular form of cholesterol, could be useful for treating Alzheimer's disease.1,2 The findings reveal two cholesteryl ester metabolism enzymes, ACAT1 and CETP, as potential AD targets and could represent a repurposing opportunity for a quartet of pharma companies that have studied the enzymes in the cardiovascular space.Cholesteryl esters consist of interlinked molecules of cholesterol and are the primary form of cholesterol in the plasma membrane and outside the cell. Cholesteryl esters are made in the endoplasmic reticulum by sterol O-acyltransferase 1 (SOAT1; ACAT1).Cholesteryl ester transfer protein (CETP) controls the flow of cholesterol between two types of lipoprotein particles, which are proteinlipid complexes that move cholesterol between cells. CETP shuttles cholesteryl esters from high-density lipoprotein (HDL) particles to low-density lipoprotein (LDL) particles.Hints of a role for cholesterol transport in AD arose in the 1990s when human genetic studies identified variants of apolipoprotein E (APOE), the protein component of lipoprotein particles, as key genetic risk factors.Together, cholesterol acyltransferase and CETP act to increase cholesterol levels in cardiovascular disease-linked LDL particles and for this reason have been considered good targets for dyslipidemia drugs.Although the precise role of lipoprotein particles in AD pathogenesis is under debate, 3 the new findings "point to the intracellular esterification process" as a targetable space upstream of APOE, said Samuel Gandy, professor of neurology and psychiatry at Mount Sinai School of Medicine. ACAT1 in mouseThe Dartmouth group focused on ACAT1's role in AD and built on earlier findings from Massachusetts General Hospital (MGH) showing that a discontinued cholesterol acyltransferase inhibitor, Pfizer Inc.'s CP-113,818, reduced AD pathology in mice. 4 Team leader Ta-Yuan Chang, professor of biochemistry at Dartmouth, said it has been difficult to study how cholesterol acyltransferase inhibitors improve AD pathology because there are several homologs expressed in different parts of the body. Thus, broad-spectrum inhibitors like CP-113,818 may have multiple effects inside and outside the brain.To get around this problem, Chang's team compared knockouts of the two major murine cholesterol acyltransferases, ACAT1 and ACAT2 (SOAT2). In mouse brain lysates, ACAT1 knockouts showed less enzyme activity than both wild-type mice and ACAT2 knockouts, suggesting that ACAT1 was the most relevant target in AD.The team then made ACAT1 knockout mice that overexpressed human amyloid-β precursor protein (APP), which is converted into toxic β-amyloid (Aβ) peptide fragments that form the characteristic amyloid plaques of AD. ACAT1 knockouts had lower Aβ than wildtype animals that overexpressed APP.Chang's results were published in the Proceedings of the Nationa...