TY - JOUR
T1 - Detection and Imaging of Aβ1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues
AU - Zhang, Jun
AU - Sandberg, Alexander
AU - Konsmo, Audun
AU - Wu, Xiongyu
AU - Nyström, Sofie
AU - Nilsson, K. Peter R.
AU - Konradsson, Peter
AU - LeVine, Harry
AU - Lindgren, Mikael
AU - Hammarström, Per
N1 - Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/5/17
Y1 - 2018/5/17
N2 - We revisited the Congo red analogue 2,5-bis(4′-hydroxy-3′-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimer's disease (AD) pathology comprising Aβ and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of Aβ1-42 (13–300 nm Kd) and Tau (16–200 nm Kd) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant Aβ1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for Aβ pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of Aβ fibrils.
AB - We revisited the Congo red analogue 2,5-bis(4′-hydroxy-3′-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimer's disease (AD) pathology comprising Aβ and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of Aβ1-42 (13–300 nm Kd) and Tau (16–200 nm Kd) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant Aβ1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for Aβ pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of Aβ fibrils.
KW - Alzheimer's disease
KW - amyloid ligands
KW - dyes/pigments
KW - fluorescence
KW - microscopy
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U2 - 10.1002/chem.201800501
DO - 10.1002/chem.201800501
M3 - Article
C2 - 29543355
AN - SCOPUS:85048042400
SN - 0947-6539
VL - 24
SP - 7210
EP - 7216
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 28
ER -