Analytical Chemistry· 2026Q1
A p K a-Guided BBB-Permeable NIR Fluorescent Probe for Tracking Lipid Droplets in Microglia with Neuroinflammation and Alzheimer’s Disease
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- 2026year
Short summary
A new near-infrared (NIR) fluorescent probe, BTDN, has been developed to track lipid droplet (LD) accumulation in microglia, a key indicator of neuroinflammation and early Alzheimer's disease (AD). BTDN is designed to cross the blood-brain barrier (BBB) and shows high sensitivity to polarity changes within cells.
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Key points
- A new NIR fluorescent probe, BTDN, was developed by tuning pKa values of benzothiadiazole derivatives.
- BTDN exhibits favorable BBB permeability (24.23%) due to its pKa (7.47) and lipophilicity (log P 3.72).
- The probe offers high sensitivity to polarity changes, NIR emission (643-770 nm), a large Stokes shift (>308 nm), and good biocompatibility.
- BTDN was used to visualize dynamic LD accumulation in microglia during neuroinflammation and in AD mouse models.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Abnormal accumulation of lipid droplets (LDs), accompanied by altered microenvironmental polarity within the microglia, is closely associated with neuroinflammation and also has been increasingly recognized as an early and dynamic indicator of Alzheimer’s disease (AD). Herein, a LD-targeting polarity-sensitive blood-brain barrier (BBB)-permeable near-infrared (NIR) probe, BTDN, was screened by tuning the electron-donating substituents to modulate the pKa values of benzothiadiazole-based derivatives. Endowed with the donor−acceptor−donor (D1−A−D2) architecture and strong intramolecular charge-transfer (ICT) characteristics, the BTDN probe exhibited high sensitivity to polarity change. The BTDN probe displayed suitable physicochemical properties such as a pKa of 7.47 and lipophilicity with a log P of 3.72 for favorable BBB-penetrating efficiency with a permeability percentage of 24.23%. In addition, the BTDN probe showed advantages for fluorescence imaging including NIR emission from 643 to 770 nm with the increased polarity, Stokes shift larger than 308 nm, comparable two-photon absorption capacity with an absorption cross-section of 10 GM at 870 nm, good biocompatibility, and robust photostability. Using this multifunctional BTDN probe, the dynamic fluorescence imaging of accumulation behaviors of LDs in BV2 microglia with neuroinflammation was performed, demonstrating that LD formation may serve as a potential biomarker for neuroinflammation. Furthermore, overproduced LDs within microglia were directly observed in vivo and in tissue sections from the brains of AD mice. This work not only provides an imaging tool for dynamically characterizing LD accumulation in microglia but also provides insights into the relationship between LD accumulation in microglia and AD pathogenesis.
The authors' abstract, as published at the source. Analytical Chemistry, 2026 · DOI ↗
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Field: Biochemistry (Biochemistry, Genetics and Molecular Biology)
BiochemistryBiochemistry, Genetics and Molecular Biology