title: A distinct subfraction of Aβ is responsible for the high-affinity Pittsburgh compound B-binding site in Alzheimer's disease brain.
abstract: The positron emission tomography (PET) ligand (11) C-labeled Pittsburgh compound B (PIB) is used to image β-amyloid (Aβ) deposits in the brains of living subjects with the intent of detecting early stages of Alzheimer's disease (AD). However, deposits of human-sequence Aβ in amyloid precursor protein transgenic mice and non-human primates bind very little PIB. The high stoichiometry of PIB:Aβ binding in human AD suggests that the PIB-binding site may represent a particularly pathogenic entity and/or report local pathologic conditions. In this study, (3) H-PIB was employed to track purification of the PIB-binding site in > 90% yield from frontal cortical tissue of autopsy-diagnosed AD subjects. The purified PIB-binding site comprises a distinct, highly insoluble subfraction of the Aβ in AD brain with low buoyant density because of the sodium dodecyl sulfate-resistant association with a limited subset of brain proteins and lipids with physical properties similar to lipid rafts and to a ganglioside:Aβ complex in AD and Down syndrome brain. Both the protein and lipid components are required for PIB binding. Elucidation of human-specific biological components and pathways will be important in guiding improvement of the animal models for AD and in identifying new potential therapeutic avenues. A lipid-associated subpopulation of Aβ accounts for the high-affinity binding of Pittsburgh compound B (PIB) in Alzheimer's disease brain. Mass spectrometry of the isolated PIB-binding site from frontal cortex identified Aβ peptides and a set of plaque-associated proteins in AD but not age-matched normal brain. The PIB-binding site may represent a particularly pathogenic entity and/or report local pathologic conditions.
authors.affiliation: Center on Aging, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Matveev
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Spielmann
authors.forename: Brittney M
authors.initials: BM
authors.lastname: Metts
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Fredrick
authors.initials: F
authors.lastname: Onono
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scheff
authors.forename: Lary C
authors.initials: LC
authors.lastname: Walker
authors.forename: Harry
authors.initials: H
authors.lastname: LeVine
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000814:Aniline Compounds / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics; D004314:Down Syndrome / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D040901:Proteomics; D013844:Thiazoles / Q000378:metabolism*
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D013844:Thiazoles
keywords: ELISA; amyloid; lipids; plaque; radioreceptor assay; tau