Triple-Target Inhibition of Cholinesterase, Amyloid Aggregation, and GSK3β to Ameliorate Cognitive Deficits and Neuropathology in the Triple-Transgenic Mouse Model of Alzheimer's Disease.
10.1007/s12264-025-01354-y
- Author:
Junqiu HE
1
;
Shan SUN
1
;
Hongfeng WANG
2
;
Zheng YING
3
;
Kin Yip TAM
4
Author Information
1. Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
2. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215127, China. wanghongfeng@suda.edu.cn.
3. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215127, China. zheng.ying@suda.edu.cn.
4. Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China. kintam@um.edu.mo.
- Publication Type:Journal Article
- Keywords:
Alzheimer’s disease;
Amyloid-β aggregation;
Autophagy;
Cholinesterases;
GSK-3β;
Multi-targeted inhibitor
- MeSH:
Animals;
Alzheimer Disease/genetics*;
Mice, Transgenic;
Glycogen Synthase Kinase 3 beta/metabolism*;
Disease Models, Animal;
Mice;
Amyloid beta-Peptides/metabolism*;
Cholinesterase Inhibitors/therapeutic use*;
Humans;
Autophagy/drug effects*;
Cognitive Dysfunction/pathology*;
Neuroprotective Agents/pharmacology*
- From:
Neuroscience Bulletin
2025;41(5):821-836
- CountryChina
- Language:English
-
Abstract:
Alzheimer's disease (AD) poses one of the most urgent medical challenges in the 21st century as it affects millions of people. Unfortunately, the etiopathogenesis of AD is not yet fully understood and the current pharmacotherapy options are somewhat limited. Here, we report a novel inhibitor, Compound 44, for targeting cholinesterases, amyloid-β (Aβ) aggregation, and glycogen synthase kinase 3β (GSK-3β) simultaneously with the aim of achieving symptomatic relief and disease modification in AD therapy. We found that Compound 44 had good inhibitory effects on all intended targets with IC50s of submicromolar or better, significant neuroprotective effects in cell models, and beneficial improvement of cognitive deficits in the triple transgenic AD (3 × Tg AD) mouse model. Moreover, we showed that Compound 44 acts as an autophagy regulator by inducing nuclear translocation of transcription factor EB through GSK-3β inhibition, enhancing the biogenesis of lysosomes and elevating autophagic flux, thus ameliorating the amyloid burden and tauopathy, as well as mitigating the disease phenotype. Our results suggest that triple-target inhibition via Compound 44 could be a promising strategy that may lead to the development of effective therapeutic approaches for AD.
