title: Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence.
abstract: 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.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Dong
authors.forename: Craig S
authors.initials: CS
authors.lastname: Atwood
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Anderson
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Paul R
authors.initials: PR
authors.lastname: Carey
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D003300:Copper / Q000737:chemistry; D005260:Female; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000737:chemistry; D019216:Metals, Heavy / Q000737:chemistry* / Q000378:metabolism*; D008715:Methionine / Q000737:chemistry; D008853:Microscopy; D010084:Oxidation-Reduction; D058225:Plaque, Amyloid / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D013059:Spectrum Analysis, Raman / Q000379:methods; D014443:Tyrosine / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D019216:Metals, Heavy; D001224:Aspartic Acid; D018698:Glutamic Acid; D014443:Tyrosine; D003300:Copper; D008715:Methionine; D007501:Iron; D015032:Zinc