Premium
A distinct subfraction of Aβ is responsible for the high‐affinity Pittsburgh compound B‐binding site in Alzheimer's disease brain
Author(s) -
Matveev Sergey V.,
Spielmann Hans Peter,
Metts Brittney M.,
Chen Jing,
Oo Fredrick,
Zhu Haining,
Scheff Stephen W.,
Walker Lary C.,
LeVine Harry
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12815
Subject(s) - pittsburgh compound b , binding site , human brain , alzheimer's disease , chemistry , amyloid precursor protein , ligand (biochemistry) , biochemistry , neuroscience , biology , receptor , pathology , disease , medicine
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.