Pittsburgh Compound-B (PiB) binds amyloid ?-protein protofibrils.
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ABSTRACT:
SUBMITTER: Yamin G
PROVIDER: S-EPMC5225051 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
Pittsburgh Compound-B (PiB) binds amyloid β-protein protofibrils.
Yamin Ghiam G Teplow David B DB
Journal of neurochemistry 20161212 2
The neuropathology of Alzheimer's disease (AD) includes amyloid plaque formation by the amyloid β-protein (Aβ) and intracellular paired helical filament formation by tau protein. These neuropathogenetic features correlate with disease progression and have been revealed in brains of AD patients using positron emission tomography (PET). One of the most useful positron emission tomography imaging agents has been Pittsburgh Compound-B (PiB). However, since its introduction in 2002, substantial evide ...[more]
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Project description:The benzothiazole-aniline derivative Pittsburgh Compound B (PiB) is the prototypical amyloid affinity probe developed for the in vivo positron emission tomography (PET) detection of amyloid beta (A?) deposits in Alzheimer's disease (AD). Specific high-affinity binding sites for PiB have been found to vary among AD cases with comparable A? load, and they are virtually absent on human-sequence A? deposits in animal models, none of which develop the full phenotype of AD. PiB thus could be an informative probe for studying the pathobiology of A?, but little is known about the localization of PiB binding at the molecular or structural level. By functionalizing the 6-hydroxy position of PiB with a PEG3 spacer and a terminal alkyne (propargyl) moiety, we have developed a clickable PiB compound that was derivatized with commercially available azide-labeled fluorophores or affinity-tags using copper-catalyzed azide-alkyne cycloaddition reactions, commonly referred to as "click" chemistry. We have determined that both the clickable PiB derivative and its fluorescently labeled conjugate have low nanomolar binding affinities for synthetic A? aggregates. Furthermore, the fluorescent-PiB conjugate can effectively bind A? aggregates in human AD brain homogenates and tissue sections. By covalently coupling PiB to magnetic beads, A? aggregates were also affinity-captured from AD brain extracts. Thus, the clickable PiB derivative described herein can be used to generate a wide variety of covalent conjugates, with applications including the fluorescence detection of A?, the ultrastructural localization of PiB binding, and the affinity capture and structural characterization of A? and other cofactors from AD brains.
| S-EPMC5845826 | biostudies-literature
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