Molecular engineering of a theranostic molecule that detects Aβ plaques, inhibits Iowa and Dutch mutation Aβ self-aggregation and promotes lysosomal biogenesis for Alzheimer's disease

Ashok Iyaswamy*, Xueli Wang, Hailong Zhang, Karthick Vasudevan, Dapkupar Wankhar, Kejia Lu, Senthilkumar Krishnamoorthi, Xin-Jie Guan, Cheng-Fu Su, Jia Liu, Yuxuan Kan, Ravindran Jaganathan, Zhiqiang Deng, Hung Wing Li*, Man Shing Wong*, Min Li*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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Abstract

Extracellular clustering of amyloid-β (Aβ) and impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer’s disease (AD). There is a pressing need of finding or developing new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule namely, F-SLCOOH which can bind and detect Aβ1-42, Iowa mutation Aβ, Dutch mutation Aβ fibrils and oligomers exhibiting enhanced emission with high affinity. Importantly, F-SLCOOH can readily pass through the blood-brain barrier and show highly selective binding toward the extracellular Aβ aggregates in real-time in live animal imaging of 5XFAD mice model. In addition, high concentration of F-SLCOOH in both brain and plasma of wildtype mice after intraperitoneal administration was found. The ex vivo confocal imaging of hippocampal brain slices indicated excellent colocalization of F-SLCOOH with Aβ positive NU1, 4G8, 6E10 A11 antibodies and THS staining dye, affirming its excellent Aβ specificity and targetability. The molecular docking studies have provided an insight into the unique and specific binding of F-SLCOOH with various Aβ species. Importantly, F-SLCOOH exhibits remarkable anti-fibrillation property against toxic Aβ aggregates formation of Aβ1-42, Iowa mutation Aβ, and Dutch mutation Aβ. F-SLCOOH treatment also exerts high neuroprotective functions and promotes autophagy lysosomal biogenesis in neuronal AD cell models. In summary, the present results suggest that F-SLCOOH is a highly promising theranostic agent for diagnosis and therapeutics of AD.
Original languageEnglish
Pages (from-to)7543-7556
Number of pages14
JournalJournal of Materials Chemistry B
Volume12
Issue number31
Early online date9 Jul 2024
DOIs
Publication statusPublished - 21 Aug 2024

Scopus Subject Areas

  • Chemistry(all)
  • Materials Science(all)
  • Biomedical Engineering

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