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A distinct subfraction of A? 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 ?-amyloid (A?) deposits in the brains of living subjects with the intent of detecting early stages of Alzheimer's disease (AD). However, deposits of human-sequence A? in amyloid precursor protein transgenic mice and non-human primates bind very little PIB. The high stoichiometry of PIB:A? 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 A? 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:A? 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 A? 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 A? 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.

SUBMITTER: Matveev SV 

PROVIDER: S-EPMC4205261 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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

Matveev Sergey V SV   Spielmann Hans Peter HP   Metts Brittney M BM   Chen Jing J   Onono Fredrick F   Zhu Haining H   Scheff Stephen W SW   Walker Lary C LC   LeVine Harry H  

Journal of neurochemistry 20140728 3


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 an  ...[more]

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