Cholesterol Binding Linked to Amyloid Plaque Formation in Alzheimer’s Disease

The first cleavage is carried out by the enzyme beta-secretase and generates C99 protein. C99 is the transmembrane carboxyl-terminal domain of APP that is then cleaved by gamma-secretase to release the amyloid-beta polypeptides.

Investigators at Vanderbilt University (Nashville, TN, USA; www.vanderbilt.edu) employed nuclear magnetic resonance and electron paramagnetic resonance spectroscopy to study the structure of C99.

They reported in the June 1, 2012, issue of the journal Science that the extracellular amino terminus of C99 included a surface-embedded “N-helix” followed by a short “N-loop” connected to the transmembrane domain (TMD). The TMD was a flexibly curved alpha helix, making it well suited for cleavage by gamma-secretase. Titration of C99 revealed a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes the development of amyloid-beta plaques. Membrane-buried GXXXG motifs (where G is glycine and X is any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding.

“It has long been thought that cholesterol somehow promotes Alzheimer’s disease, but the mechanisms have not been clear,” said senior author Dr. Charles Sanders, professor of biochemistry at Vanderbilt University. “Cholesterol binding to APP and its C99 fragment is probably one of the ways it makes the disease more likely. We think that when APP does not have cholesterol around, it does not care what part of the membrane it is in, but when it binds cholesterol, that drives it to lipid rafts, where these “bad” secretases are waiting to clip it and produce amyloid-beta.”

“If you could develop a drug that blocks cholesterol from binding to APP, then you would keep the protein from going to lipid rafts” said Dr. Sanders. “Instead it would be cleaved by alpha-secretase – a ‘”good” secretase that is not in rafts and does not generate amyloid-beta. Anything that lowers amyloid-beta production should help prevent, or possibly treat, Alzheimer’s disease.”

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