High-Affinity Fluorescent Probes for the Detection of Soluble and Insoluble Aβ Deposits in Alzheimer's Disease.

Autor:	Mallesh R; Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, NH 62, Surpura Bypass Road, Karwar 342037, Rajasthan, India.; Organic and Medicinal Chemistry and Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata700 032, West Bengal, India.; National Institute of Pharmaceutical Education and Research, Kolkata, Chunilal Bhawan 168, Maniktala Main Road, Kolkata 700054, India., Khan J; Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, NH 62, Surpura Bypass Road, Karwar 342037, Rajasthan, India.; Organic and Medicinal Chemistry and Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata700 032, West Bengal, India., Gharai PK; Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, NH 62, Surpura Bypass Road, Karwar 342037, Rajasthan, India.; Organic and Medicinal Chemistry and Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata700 032, West Bengal, India., Ghosh S; Organic and Medicinal Chemistry and Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata700 032, West Bengal, India., Garg S; Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, NH 62, Surpura Bypass Road, Karwar 342037, Rajasthan, India., Arshi MU; Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, NH 62, Surpura Bypass Road, Karwar 342037, Rajasthan, India., Ghosh S; Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, NH 62, Surpura Bypass Road, Karwar 342037, Rajasthan, India.; Organic and Medicinal Chemistry and Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata700 032, West Bengal, India.; National Institute of Pharmaceutical Education and Research, Kolkata, Chunilal Bhawan 168, Maniktala Main Road, Kolkata 700054, India.
Jazyk:	angličtina
Zdroj:	ACS chemical neuroscience [ACS Chem Neurosci] 2023 Apr 04. Date of Electronic Publication: 2023 Apr 04.
DOI:	10.1021/acschemneuro.2c00787
Abstrakt:	The overproduction and deposition of the amyloid-β (Aβ) aggregates are accountable for the genesis and development of the neurologic disorder Alzheimer's disease (AD). Effective medications and detection agents for AD are still deficient. General challenges for the diagnosis of Aβ aggregates in the AD brain are (i) crossing the blood-brain barrier (BBB) and (ii) selectivity to Aβ species with (iii) emission maxima in the 500-750 nm region. Thioflavin-T (ThT) is the most used fluorescent probe for imaging Aβ fibril aggregates. However, because of the poor BBB crossing (log  P = -0.14) and short emission wavelength (482 nm) after binding with Aβ fibrils, ThT can be limited to in vitro use only. Herein, we have developed Aβ deposit-recognizing fluorescent probes (ARs) with a D-π-A architecture and a longer emission wavelength after binding with Aβ species. Among the newly designed probes, AR-14 showed an admirable fluorescence emission (>600 nm) change after binding with soluble Aβ oligomers (2.3-fold) and insoluble Aβ fibril aggregates (4.5-fold) with high affinities K d = 24.25 ± 4.10 nM; K a = (4.123 ± 0.69) × 10 7 M -1 for fibrils; K d = 32.58 ± 4.89 nM; and K a = (3.069 ± 0.46) × 10 7 M -1 for oligomers with high quantum yield, molecular weight of <500 Da, reasonable log  P = 1.77, stability in serum, and nontoxicity, and it can cross the BBB efficiently. The binding affinity of AR-14 toward Aβ species is proved by fluorescence binding studies and fluorescent staining of 18-month-old triple-transgenic (3xTg) mouse brain sections. In summary, the fluorescent probe AR-14 is efficient and has an admirable quality for the detection of soluble and insoluble Aβ deposits in vitro and in vivo .
Databáze:	MEDLINE
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