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ACS Chem Neurosci. 2016 Nov 16;7(11):1474-1481. Epub 2016 Sep 1.

A Smart Near-Infrared Fluorescence Probe for Selective Detection of Tau Fibrils in Alzheimer's Disease.

Author information

1
Department of Integrative Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University , Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea.
2
Center for Neuro-Medicine, Korea Institute of Science and Technology , 39-1 Hawolgok-dong, Seoungbuk-gu, Seoul 136-791, Korea.
3
Veteran's Affairs Boston Healthcare System , Boston, Massachusetts 02130, United States.
4
Boston University Alzheimer's Disease Center and Department of Neurology, Boston University School of Medicine , Boston, Massachusetts 02118, United States.
5
Department of Biological Chemistry, Korea University of Science and Technology , Youseong-gu, Daejeon 305-350, Korea.

Abstract

Development of a novel, tau-selective smart near-infrared fluorescence (NIRF) probe was attempted by combining the previously identified core scaffold 3,5-dimethoxy-N,N-dimethylaniline-4-yl moiety, with the characteristic donor-π-acceptor architecture of the smart NIRF Aβ probes DANIR-2c and MCAAD-3. A series of compounds (2 and 3) were prepared, which were identified as "turn-on" NIRF probes for the visual detection of tau aggregates and Aβ fibrils (λem = 650 nm, Stokes shifts = 70-110 nm). In particular, combination of the 3,5-dimethoxy-N,N-dimethylanilin-4-yl moiety and the donor part of MCAAD-3 endowed the resulting probes, 3g and 3h, with significant selectivity toward tau aggregates (selectivity for tau over Aβ = 5.7 and 3.8); they showed much higher fluorescence intensities upon binding to tau aggregates (FItau = 49 and 108) than when bound to Aβ fibrils (FI = 9 and 28). Quantitative analysis of binding affinities and fluorescence properties of 3g and 3h revealed that microenvironment-sensitive molecular rotor-like behavior, rather than binding affinity to the target, is responsible for their selective turn-on fluorescence detection of tau fibrils. Selective fluorescent labeling of tau fibrils by 3g and 3h was further demonstrated by immunofluorescence staining of human Alzheimer's disease brain sections, which showed colocalization of the probes (3g and 3h) and phosphorylated tau antibody.

KEYWORDS:

Alzheimer’s disease; Near-infrared fluorescence (NIRF); molecular rotor; smart probe; tau fibrils

PMID:
27576176
DOI:
10.1021/acschemneuro.6b00174
[Indexed for MEDLINE]

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