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Abstract
The aggregation of amyloid beta (Aβ) proteins in senile plaques is a critical event during the development of Alzheimer's disease, and the postmortem detection of Aβ-rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools. In animal models, fluorescence imaging can be employed to follow the progression of the disease, and among the different imaging methods, two-photon microscopy (TPM) has emerged as one of the most powerful. To date, several near-infrared-emissive two-photon dyes with a high affinity for Aβ fibrils have been developed, but there has often been a tradeoff between excellent two-photon cross-sections and large fluorescence signal-to-background ratios. In the current work, we introduced a twisted intramolecular charge state (TICT)-based de-excitation pathway, which results in a remarkable fluorescence increase of around 167-fold in the presence of Aβ fibrils, while maintaining an excellent two-photon cross section, thereby enabling high-contrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de-excitation in two-photon fluorophores may represent a general method to overcome the tradeoff between probe brightness and signal-to-background ratio.

Author information

Shin J1, Verwilst P1, Choi H2, Kang S3,4, Han J5, Kim NH6, Choi JG7, Oh MS7, Hwang JS8, Kim D3,6,9, Mook-Jung I2, Kim JS1.
1
Department of Chemistry, Korea University, Seoul, 02841, Korea.
2
Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Korea.
3
Department of Anatomy and Neurobiology, College of Medicine, Korea.
4
Department of Pathology, College of Medicine, Korea.
5
Department of Biological Sciences, Laboratory of Stem Cell Research and Biotechnology, Hyupsung University, Hwasung-si, 18330, Korea.
6
Department of Biomedical Science, Graduate School, Korea.
7
Department of Life and Nanopharmaceutical Sciences, Korea.
8
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, 41061, Korea.
9
Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Korea.