In vitro characterization of Pittsburgh compound-B binding to Lewy bodies.
Dementia with Lewy bodies (DLB) is pathologically characterized by the presence of alpha-synuclein-containing Lewy bodies within the neocortical, limbic, and paralimbic regions. Like Alzheimer's disease (AD), Abeta plaques are also present in most DLB cases. The contribution of Abeta to the development of DLB is unclear. [11C]-Pittsburgh compound B ([11C]-PIB) is a thioflavin-T derivative that has allowed in vivo Abeta burden to be quantified using positron emission tomography (PET). [11C]-PIB PET studies have shown similar high cortical [11C]-PIB binding in AD and DLB subjects. To establish the potential binding of PIB to alpha-synuclein in DLB patients, we characterized the in vitro binding of PIB to recombinant human alpha-synuclein and DLB brain homogenates. Analysis of the in vitro binding studies indicated that [3H]-PIB binds to alpha-synuclein fibrils but with lower affinity than that demonstrated/reported for Abeta(1-42) fibrils. Furthermore, [3H]-PIB was observed to bind to Abeta plaque-containing DLB brain homogenates but failed to bind to DLB homogenates that were Abeta plaque-free ("pure DLB"). Positive PIB fluorescence staining of DLB brain sections colocalized with immunoreactive Abeta plaques but failed to stain Lewy bodies. Moreover, image quantification analysis suggested that given the small size and low density of Lewy bodies within the brains of DLB subjects, any contribution of Lewy bodies to the [11C]-PIB PET signal would be negligible. These studies indicate that PIB retention observed within the cortical gray matter regions of DLB subjects in [11C]-PIB PET studies is largely attributable to PIB binding to Abeta plaques and not Lewy bodies.
Fodero-Tavoletti
Michelle T
MT
Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Smith
David P
DP
McLean
Catriona A
CA
Adlard
Paul A
PA
Barnham
Kevin J
KJ
Foster
Lisa E
LE
Leone
Laura
L
Perez
Keyla
K
Cortés
Mikhalina
M
Culvenor
Janetta G
JG
Li
Qiao-Xin
QX
Laughton
Katrina M
KM
Rowe
Christopher C
CC
Masters
Colin L
CL
Cappai
Roberto
R
Villemagne
Victor L
VL
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism*; D001665:Binding Sites; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D016631:Lewy Bodies / Q000502:physiology*; D020961:Lewy Body Disease / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D049268:Positron-Emission Tomography; D013844:Thiazoles / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D013844:Thiazoles; D051844:alpha-Synuclein