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. 2025 Sep;62(9):11403-11414.
doi: 10.1007/s12035-025-04982-7. Epub 2025 Apr 26.

Multi-Target Inhibitor of ZJQ- 3 F Against AChE/BACE1/GSK3β Targets Improves the Cognitive Impairment of APP/PS1/Tau Triple-Transgenic Mouse Models of Alzheimer's Disease

Nan Wang  1   2 , Xin-Zhu Li  1 , Xiao-Wen Jiang  3 , Xin-Yue Ning  1 , Li-Jun Zhou  1 , Wen-Jie Liu  1 , Qiong Wu  2 , Xin-Peng Wang  1 , Yu Xing  1 , Zhen-Tong Qi  1 , Zi-Hua Xu  1   2 , Hong-Tao Song  4   5 , Qing-Chun Zhao  6   7
Affiliations

Multi-Target Inhibitor of ZJQ- 3 F Against AChE/BACE1/GSK3β Targets Improves the Cognitive Impairment of APP/PS1/Tau Triple-Transgenic Mouse Models of Alzheimer's Disease

Nan Wang et al. Mol Neurobiol. 2025 Sep.

Erratum in

Abstract

Background: Alzheimer's disease (AD) is a multifactorial neuropathology characterized by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) and cholinergic system dysfunction. At present, there is no effective treatment strategy for AD. Our previous research showed that ZJQ-3F acts as an inhibitor of AChE/BACE1/GSK3β, and showed good blood-brain barrier permeability, appropriate bioavailability and oral safety. In order to further study, the protective effect of ZJQ-3F on APP/PS1/Tau transgenic mice was determined.

Methods: APP/PS1/Tau transgenic mice model of AD was treated with ZJQ-3F from the age of 8 to 12 months, and then behavioral tests was conducted. Western blot, immunohistochemistry and immunofluorescence staining were used to evaluate the level of tau protein, Aβ plaques and synaptic function.

Results: Our results revealed that administration of ZJQ-3F could improve the cognitive function of APP/PS1/Tau transgenic mice. In addition, compared with APP/PS1/Tau mice, the protein expression levels of tau protein phosphorylation site at Ser396, Thr212 and Thr181 in the cortex and hippocampus of ZJQ-3F treated mice was significantly decreased. Moreover, the results showed that ZJQ-3F significantly reduced the deposition of Aβ in the cortex and hippocampus. Furthermore, the results indicated that the protein expression levels of PSD95, SYP and SYT in the cortex and hippocampus were increased markedly after ZJQ-3F was given.

Conclusions: Our studies suggest that the chronic administration of ZJQ-3F can improve learning and memory ability, reduce tau protein phosphorylation, reduce Aβ deposition and improve synaptic dysfunction in APP/PS1/Tau transgenic model of AD, indicating that ZJQ-3F can be used as a multi-target inhibitor to slow down the progress of AD.

Keywords: AChE; APP/PS1/Tau; Alzheimer’s disease; BACE1; GSK3β; Multi-target.

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Conflict of interest statement

Declarations. Ethical Approval: All animal experiments were subject to approval by the Institutional Animal Care and Use Committee at Shenyang Pharmaceutical University. Consent to Participate: Not applicable. Consent for Publication: All authors agreed with the content and gave explicit consent to the formulation and publication of this work. Competing interests: The authors declare no competing interests.

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