CDU

People who pop cholesterol-lowering statin pills – the likes of Mevacor, Zocor and Lipitor – do so to lower their risk of incurring atherosclerosis. This blockage of coronary arteries feeding the heart and brain causes cardiovascular disease and ischemic stroke, the prime serial killers in Western industrial society.

It's now beginning to be common knowledge that high cholesterol levels also threaten the onset of Alzheimer's disease (AD), another of cholesterol's pathogenic targets. The smoking gun that AD fires at its brain neurons is a runty molecule about 40 amino acids long, called amyloid-beta peptide. It leaves fingerprints and footprints in and around the senile neuritic plaques and fibrillary tangles that are the hallmarks of moribund AD neurons.

It's also becoming obvious that high consumption of fatty foods and low fidelity to physical exercise, have direct consequences for incurring AD. But the metabolic connection between these couch-potato lifestyles and the heightening prevalence of the neurodegenerative disease is only beginning to emerge from the laboratory.

"High cholesterol levels correlate with poor prognosis in conditions such as coronary heart disease and Alzheimer's disease," said research neurologist Dora Kovacs, at Harvard-affiliated Massachusetts General Hospital (Boston, Massachusetts). "But whether or not cholesterol is harmless," she added, "also depends on where it goes within cells. Although high blood cholesterol levels are associated with atherosclerosis and stroke, and recently with Alzheimer's disease, there is no direct cause-and-effect link between cholesterol deposits and AD – just indirect and genetic evidence."

Kovacs is corresponding author of a paper in the October 2001 issue of Nature Cell Biology."What we reported," she said, "was a correlation between one particular form of cholesterol, namely cholesteryl-ester, and how much beta amyloid is generated in cells. We didn't really show that cholesteryl-ester actually modulated amyloid-beta generation, but only the correlation." She added that there are two substrates: acyl coenzyme A and cholesterol. "Then a key enzyme called ACAT puts the acyl group over the cholesterol."

As her group reported, that acyl-coenzyme A, "the molecule that generates cholesteryl-ester, was inhibited, and amyloid-beta was reduced. Cholesteryl-ester levels have never before been associated with amyloid-beta generation."

Kovacs said free cholesterol "is a part of all cell membranes, from which it is transferred as insoluble lipid droplets into the cells' interior cytoplasm. This process is controlled by acyl-coenzyme A:cholesterol acyltransferase [ACAT]. Cholesteryl-ester is a key combination of cholesterol and long-chain fatty acids that resides in the cell's endoplasmic reticulum." One effect, she added, "is that cholesteryl-esters become completely insoluble and cannot even stay in the membranes. Instead, they turn into insoluble lipids or blocks inside the cytoplasm."

When ACAT, "which is responsible for the generation of amyloid-beta peptide, is inhibited, it can reduce A-beta generation," Kovacs said. "This is novel because ACAT is a potential therapeutic target for treating AD."

She cautioned that "Our experiments so far were done only in vitro, in cell culture, because we haven't had access to inhibitors so far. Unable to try them on transgenic animals, we don't even know if ACAT blockers act at the brain, or how stable they are. These small, insoluble, synthetic inhibitors mimic one of the ACAT's substrates. Basically, it's a pharmacological competitive inhibitor of ACAT. We obtained ours from one of the several pharmaceutical companies that are trying to mimic these substrates."

Kovacs said in vivo studies would start before the end of September in transgenic mice that overexpress APP – amyloid precursor protein. "That's the long molecule from which the short amyloid-beta peptide is cleaved off," she said. "These mice have elevated A-beta, so we can measure the effect the ACAT inhibitors have in the animals as to A-beta generation."

Another novelty in the research paper, she said, "is that prior to our study, people were looking at just overall cholesterol levels in cells, and the effect they had on beta-amyloid generation. But inside the cells, cholesterol exists in different forms, free in the membrane, and the cholesteryl esters in different cellular compartments – different distribution of cholesterol, and the differing forms correlated with generation of amyloid-beta.

"Our finding that inhibiting one particular enzyme nobody had thought about before can lower A-beta production actually fits neatly with previous studies by others of cholesterol-lowering statins," Kovacs noted. "Two papers at the end of last year on retrospective clinical effects of statins on onset of AD reported that patients who were taking statins were found to be less at risk for developing the disease. So statins actually inhibit the generation of free cholesterol. High levels of cholesterol increase amyloid beta generation, presumably because at the cellular level they correspond to high levels ofcholesteryl-esters."