Evidence map›Paper›PMID 41645328›Full record

ArticleAlzheimer's research & therapy2026

ISX9 activates the Wnt/β-catenin signaling pathway and exerts neuroprotective effects in Alzheimer's disease.

Jianhong Xiao, Yi Liu, Mingli Peng, Jiaying Ma, Shujing Lei, Yuexuan Chen, Shanshan Liu, Xibao Zhao, Desheng Lu, Qi Sun

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Jianhong Xiao *Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Yi Liu *Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Mingli Peng *Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Jiaying MaMarshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Shujing LeiMarshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Yuexuan ChenMarshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Shanshan LiuMarshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Xibao ZhaoMarshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Desheng LuMarshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China. delu@szu.edu.cn.
Qi SunMarshall Laboratory of Biomedical Engineering, Department of Pharmacology, International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China. sunqi@szu.edu.cn.

Funding

National Natural Science Foundation of China 82273485National Natural Science Foundation of China 82470591Natural Science Foundation of Guangdong Province 2022A1515010598 and 2024A1515012466Shenzhen Basic Research Program JCYJ20240813142838050
6 · The paper itself

Abstract

backgroundDefective Wnt/β-catenin signaling is closely associated with the pathogenesis of Alzheimer's disease (AD), thus validating this pathway as a therapeutic target for AD. ISX9 is a potent agonist of the Wnt/β-catenin pathway. However, it remains unknown whether ISX9 exerts anti-AD effects by enhancing the Wnt/β-catenin signaling pathway. We therefore explored the neuroprotective potential of ISX9 using both hippocampal neuron-derived HT22 cells and 5×FAD transgenic mouse model of AD.

methodsIn HT22 cells, we employed the SuperTOPFlash reporter gene, Co-IP and Western blot assays to investigate the mechanism by which ISX9 activates the Wnt signaling pathway. The effects of ISX9 on the biological behavior of HT22 cells were further evaluated through MTT, BrdU and IF staining. To study the therapeutic effect of ISX9 on AD, six-month-old 5×FAD transgenic mice were randomly divided into four groups: WT, WT/ISX9, AD and AD/ISX9. The mice were intraperitoneally injected with ISX9 or vehicle at an interval of one day for 2 months. Behavioral tests were conducted to evaluate the cognitive and learning abilities of mice, while the expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, blood-brain barrier (BBB)-related proteins and the components of Wnt/β-catenin signaling were investigated.

resultsOur results demonstrated that ISX9 potently activated Wnt/β-catenin signaling by promoting the association of LRP6 with AXIN1, and increased the viability and proliferation of hippocampal cells. At the behavioral level, ISX9 improved learning and memory abilities in 5×FAD mice, and ameliorated hippocampal neuronal damage. Furthermore, ISX9 treatment effectively reduced the expression of Aβ peptides, total Tau, and phosphorylated Tau (S404) proteins in the AD mice. Mechanistically, ISX9 exhibited its neuroprotective effects, activating the Wnt/β-catenin signaling pathway via potentiating the interaction of LRP6 with AXIN1, upregulating the expression of BBB-related proteins and downregulating neuroinflammatory factors in AD mice.

conclusionOur findings indicate that ISX9 potently activates the Wnt/β-catenin signaling pathway and confers cognitive protection in hippocampal cells and AD mice. This compound may serve as a promising therapeutic agent for the treatment of AD.

Indexed as

Alzheimer DiseaseHeterocyclic Compounds, 3-RingNeuroprotective AgentsWnt Signaling PathwayAmyloid beta-PeptidesAnimalsbeta CateninDisease Models, AnimalHippocampusHumansMaleMiceMice, TransgenicNeuronsAmyloid beta-Peptidesbeta CateninHeterocyclic Compounds, 3-RingNeuroprotective AgentsAlzheimer’s diseaseAXIN1ISX9LRP6Wnt/β-catenin signaling

Identifiers

PMID41645328
PMCPMC12973582

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.