Abstract
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 (Kd) 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 (EC50 ) 9 nM). In contrast, the interactions of 1 were weaker toward artificially prepared aggregates of the nonphosphorylated tau protein (n-Tau; EC50 ) 80 nM) and Aγ1-42 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-γ peptides, confirming our strategy toward the rational design of a molecular probe for the selective fluorescence detection of NFTs in brain tissue sections.
Original language | English |
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Pages (from-to) | 6543-6548 |
Number of pages | 6 |
Journal | Journal of the American Chemical Society |
Volume | 131 |
Issue number | 18 |
DOIs | |
Publication status | Published - May 13 2009 |
Externally published | Yes |
All Science Journal Classification (ASJC) codes
- Catalysis
- Chemistry(all)
- Biochemistry
- Colloid and Surface Chemistry