Fluorescent BODIPY-based Zn(II) complex as a molecular probe for selective detection of neurofibrillary tangles in the brains of Alzheimer's disease patients.
We have developed a new fluorescent binuclear Zn(II) complex for the detection of neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, a representative hallmark of Alzheimer's disease (AD). The probe 1 incorporates a fluorescent BODIPY unit and two Zn(II)-2,2'-dipicolylamine (Dpa) complexes as a binding site for phosphorylated amino acid residues. Using fluorescence titration to evaluate the binding and sensing properties of 1 toward several phosphorylated peptide segments derived from hyperphosphorylated tau protein, we found that 1 binds preferentially to peptides presenting phosphorylated groups at the i and i+4 positions with dissociation constants (K(d)) in the micromolar range. Fluorescence titration with an artificially prepared aggregate of the phosphorylated tau protein (p-Tau) revealed that 1 binds strongly to p-Tau (EC(50) = 9 nM). In contrast, the interactions of 1 were weaker toward artificially prepared aggregates of the nonphosphorylated tau protein (n-Tau; EC(50) = 80 nM) and Abeta(1-42) fibrils (EC(50) = 650 nM). Histological imaging of a hippocampus tissue section obtained from an AD patient revealed that 1 fluorescently visualizes deposits of NFTs and clearly discriminates between NFTs and the amyloid plaques assembled from amyloid-beta peptides, confirming our strategy toward the rational design of a molecular probe for the selective fluorescence detection of NFTs in brain tissue sections.
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura campus, Kyoto 615-8510, Japan.
Akio
A
Ojida
Takashi
T
Sakamoto
Masa-aki
MA
Inoue
Sho-hei
SH
Fujishima
Guy
G
Lippens
Itaru
I
Hamachi
D000544:Alzheimer Disease / Q000175:diagnosis*; D001896:Boron Compounds; D001921:Brain / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D015336:Molecular Probe Techniques; D016874:Neurofibrillary Tangles / Q000473:pathology*; D010766:Phosphorylation; D015032:Zinc; D016875:tau Proteins / Q000032:analysis / Q000378:metabolism
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D016875:tau Proteins; D015032:Zinc