New Research Points to Role of Cholesterol in Alzheimer’s

New Research Points to Role of Cholesterol in Alzheimer’s

By JANICE WOOD Associate News Editor 

Reviewed by John M. Grohol, Psy.D. on June 1, 2012

The molecular structure of a protein involved in Alzheimer’s disease — and the surprising discovery that it binds cholesterol — could lead to new therapies for the disease, according to new research.

Charles Sanders, Ph.D., professor of biochemistry, and colleagues at Vanderbilt University recently determined the structure of part of the amyloid precursor protein (APP) — the source of amyloid-beta, which characterizes Alzheimer’s disease.

Amyloid-beta clumps together into oligomers that kill neurons, causing dementia and memory loss. The amyloid-beta oligomers eventually form plaques in the brain, one of the hallmarks of Alzheimer’s, the researchers note.

“Anything that lowers amyloid-beta production should help prevent, or possibly treat, Alzheimer’s disease,” Sanders said.

Amyloid-beta production requires two “cuts” of the APP protein, he said. The first cut, by the enzyme beta-secretase, generates the C99 protein, which is then cut by gamma-secretase to release amyloid-beta. The Vanderbilt researchers used nuclear magnetic resonance and electron paragmagnetic resonance spectroscopy to determine the structure of C99.

The researchers said they were surprised to discover what appeared to be a “binding” domain in the protein.

Based on previously reported evidence that cholesterol promotes Alzheimer’s disease, they suspected that cholesterol might be the binding partner.

The researchers used a model membrane system called “bicelles” that Sanders developed as a postdoctoral fellow to demonstrate that C99 binds cholesterol.

“It has long been thought that cholesterol somehow promotes Alzheimer’s disease, but the mechanisms haven’t been clear,” Sanders said. “Cholesterol binding to APP and its C99 fragment is probably one of the ways it makes the disease more likely.”

Sanders and his team propose that cholesterol binding moves APP to special regions of the cell membrane called “lipid rafts,” which contain “cliques of molecules that like to hang out together,” he said.

“We think that when APP doesn’t have cholesterol around, it doesn’t care what part of the membrane it’s in,” Sanders said. “But when it binds (to) cholesterol, that drives it to lipid rafts, where these ‘bad’ secretases are waiting to clip it and produce amyloid-beta.”

The findings suggest a new strategy to reduce amyloid-beta production, he said.
“If you could develop a drug that blocks cholesterol from binding to APP, then you would keep the protein from going to lipid rafts,” he said. “Instead it would be cleaved by alpha-secretase — a ‘good’ secretase that isn’t in rafts and doesn’t generate amyloid-beta.”

Drugs that inhibit beta- or gamma-secretase to limit amyloid-beta production have been developed and tested, but they have toxic side effects, the researchers note.

A drug that blocks cholesterol binding to APP may be more effective in reducing amyloid-beta levels and in preventing, or treating, Alzheimer’s disease, the researchers conclude.

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