Linking Alzheimer’s And Cholesterol

Using NMR and other spectroscopy techniques, researchers at Vanderbilt University School of Medicine have found that amyloid precursor protein (APP)—the macromolecule that fragments and then clumps together in the brains of patients with Alzheimer’s disease—binds cholesterol (Science, DOI: 10.1126/science.1219988). Scientists have long suspected a link between elevated cholesterol levels and Alzheimer’s, says Charles R. Sanders, the Vanderbilt team’s leader, but how cholesterol promotes the neurodegenerative disease has been “murky.” Now, Sanders and his group have provided a new clue by determining the structure of C99, a cell-membrane-spanning segment of APP, and by mapping the site where it binds to cholesterol. The researchers found that C99 contains a curved, yet flexible, helical portion that spans the cell membrane and binds cholesterol with the help of a GXXXG sequence (where G is glycine, and X is any amino acid). They hypothesize that when C99 (or APP) binds cholesterol, the molecule moves the protein into cholesterol-rich areas, called lipid rafts, on the cell surface. The enzyme γ-secretase, which hangs out in these regions, then cleaves C99, forming the smaller amyloid-β fragments that characterize Alzheimer’s.