Alzheimer's disease (AD) is characterized by the deposition of
amyloid plaques in the parenchyma and vasculature of the brain. Although previous analytical studies have provided much information about the composition and structure of synthetic
amyloid-beta fibrils, there is, surprisingly, a dearth of data on intact
amyloid plaques from AD brain. Therefore, to elucidate the structure and detailed composition of isolated
amyloid plaque cores, we utilized a high-resolution, nondestructive technique, Raman microscopy. The data are of very high quality and contain detailed information about
protein composition and conformation, about post-translational modification, and about the chemistry of
metal binding sites. Remarkably, spectra obtained for
senile plaque (SP) cores isolated from AD brain are essentially identical both within and among brains. The Raman data show for the first time that the SP cores are composed largely of
amyloid-beta and confirm inferences from X-ray studies that the structure is beta-sheet with the additional possibility that this may be present as a parallel beta-helix. Raman bands characteristic of
methionine sulfoxide show that extensive
methionine oxidation has occurred in the intact plaques. The Raman spectra also demonstrate that Zn(II) and Cu(II) are coordinated to
histidine residues in the SP cores, at the side chains' N(tau) and N(pi) atoms, respectively. Treatment of the
senile plaques with the
chelator ethylenediaminetetraacetate reverses Cu binding to SP histidines and leads to a broadening of
amide features, indicating a "loosening" of the beta-structure. Our results indicate that Abeta in vivo is a
metalloprotein, and the loosening of the structure following chelation treatment suggests a possible means for the solubilization of
amyloid deposits. The results also reveal a direct chemical basis for oxidative damage caused by
amyloid-beta protein in AD.