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June 01, 2012

Cholesterol's Role in Promoting Alzheimer’s Discovered

by Jessica Berman

Scientists have discovered what they believe to be a major piece of the puzzle in the development of Alzheimer’s disease, a degenerative brain disorder that causes memory loss, mental decline and eventual death.  The finding sheds new light on the role played by cholesterol in triggering the disease, and could potentially lead to new, life-saving treatments.

There's been plenty of evidence gathered in recent years that cholesterol promotes Alzheimer’s disease.  What wasn't clear was how it does this. Cholesterol is a fatty substance found in tissue that’s essential for normal body functioning. But in the brain, experts have suspected that cholesterol plays a unique biochemical role in the onset of Alzheimer’s.

Researchers at Vanderbilt University in Nashville, Tennessee have described for the first time the molecular structure of a protein, called amyloid precursor protein, or APP. That is the initial source of amyloid beta, the toxic protein that forms clumps on the brain cells of Alzheimer's victims, causing memory loss and dementia.

Investigators discovered that the process that produces amyloid-beta involves two enzyme “cuts” to the APP molecule; the first enzyme cut generates a protein fragment called C99, which is then cut by a second enzyme to release amyloid-beta.

Using magnetic resonance imaging and spectroscopy, the scientists were surprised to discover that the C99 protein chemically attaches to cholesterol. Armed with previously reported evidence of the role of cholesterol in Alzheimer’s disease, they created a model of C99 that confirmed it binds to cholesterol and is essential to the disease process.

Lead researcher Charles Sanders likens this new understanding of cholesterol’s role in Alzheimer’s disease to finding a piece of a jigsaw puzzle.

“And you know ..certain parts of the puzzle come together first," Sanders says. "And then there will be the missing piece that links the sections together.  And what we did I think is sort of like one of these missing pieces of the puzzle.  And it doesn’t link together all pieces of the puzzle. But it does link certain pieces that haven’t been put together before.”

Sanders, a biochemist at Vanderbilt, says cholesterol adheres to C99 much like Velcro. It carries the protein to special regions of brain cell membranes, where it comes into contact with the enzymes that then cut the C99 into amyloid-beta, triggering Alzheimer's. Sanders says anything that prevents this binding of cholesterol and C99 should also prevent, or treat, Alzheimer’s disease.

For example, specially targeted cholesterol-lowering drugs might be developed that could penetrate the “blood brain barrier,” a sheath of cells and tiny capillaries separating blood in the central nervous system from circulating blood to protect the brain from microbes and toxic substances.  
 
Another challenge, according to Sanders, would be getting treatments to people before they develop symptoms.

“One of the problems is that once the person has Alzheimer’s disease, it may be very difficult to intervene using this anti-cholesterol route," he says. "And so, ideally, what you’d would want to be doing is taking these sort of drugs earlier in life before you ever get to the point where you are getting disease symptoms.”