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.

Apr 26, 2025Molecular neurobiology

A Drug Targeting Multiple Alzheimer's-Related Enzymes Improves Memory Problems in Mice with Alzheimer's-Like Brain Changes

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Abstract

ZJQ-3F may improve cognitive function in a mouse model of Alzheimer's disease.

ZJQ-3F treatment improved learning and memory abilities in APP/PS1/Tau transgenic mice.
Phosphorylation levels of tau protein at Ser396, Thr212, and Thr181 were significantly lower in treated mice.
ZJQ-3F significantly reduced amyloid-beta plaque accumulation in the brain regions studied.
Synaptic protein levels (PSD95, SYP, SYT) increased in the cortex and hippocampus after ZJQ-3F treatment.
Chronic administration of ZJQ-3F may act as a multi-target approach to slow Alzheimer's progression.

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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.

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