TY - JOUR
T1 - 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
AU - Iyaswamy, Ashok
AU - Wang, Xueli
AU - Zhang, Hailong
AU - Vasudevan, Karthick
AU - Wankhar, Dapkupar
AU - Lu, Kejia
AU - Krishnamoorthi, Senthilkumar
AU - Guan, Xin-Jie
AU - Su, Cheng-Fu
AU - Liu, Jia
AU - Kan, Yuxuan
AU - Jaganathan, Ravindran
AU - Deng, Zhiqiang
AU - Li, Hung Wing
AU - Wong, Man Shing
AU - Li, Min
N1 - Funding Information:
This study was supported by the Research Committee of Hong Kong Baptist University (CRMS/23-24/05) and Matching Proof-of-Concept Fund (HKBU-MPCF-003-2022-23). Hong Kong Health and Medical Research Fund (HMRF/17182541, HMRF/17182551, HMRF/09203776, HMRF/21221301) and the General Research Fund from Research Grant Council (HKBU 12302620, 12302021, and 12101022). HWL is grateful for the support of the Direct Grant from the Chinese University of Hong Kong.
Publisher Copyright:
© 2024 The Royal Society of Chemistry.
PY - 2024/8/21
Y1 - 2024/8/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85198075136&partnerID=8YFLogxK
U2 - 10.1039/D4TB00479E
DO - 10.1039/D4TB00479E
M3 - Journal article
SN - 2050-750X
VL - 12
SP - 7543
EP - 7556
JO - Journal of Materials Chemistry B
JF - Journal of Materials Chemistry B
IS - 31
ER -