A distinct subfraction of Aβ is responsible for the high-affinity Pittsburgh compound B-binding site in Alzheimer's disease brain

Sergey V. Matveev, Hans Peter Spielmann, Brittney M. Metts, Jing Chen, Fredrick Onono, Haining Zhu, Stephen W. Scheff, Lary C. Walker, Harry LeVine

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The positron emission tomography (PET) ligand 11C-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, 3H-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.

Original languageEnglish (US)
Pages (from-to)356-368
Number of pages13
JournalJournal of neurochemistry
Volume131
Issue number3
DOIs
StatePublished - Aug 17 2014
Externally publishedYes

Keywords

  • amyloid
  • ELISA
  • lipids
  • plaque
  • radioreceptor assay
  • tau

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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