What is the clinical evidence from this study?

Study design: RCT. Population: Female 5×FAD transgenic mice with Alzheimer's disease at symptomatic phase (6 months old) (n=40). Intervention: ISX9 vs. vehicle (10% DMSO and 90% corn oil) intraperitoneal injection. Primary outcome: Cognitive and learning abilities assessed by Morris water maze, novel object recognition, and Y-maze tests.

What does this research mean for the field?

ISX9 administration improves learning and memory abilities in 5×FAD transgenic mice compared to vehicle treatment. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

The aim is to evaluate if ISX9 enhances Wnt/β-catenin signaling and provides neuroprotection in Alzheimer’s disease models.

February 8, 2026Alzheimer s Research & Therapy0 citationsOpen Access

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

JXJianhong Xiao YLYi LIU MPMingli Peng

Key Result

ISX9 improved learning and memory abilities and mitigated hippocampal neuronal damage in 5×FAD Alzheimer's disease mice after 2 months of treatment.

Key Points

The aim is to evaluate if ISX9 enhances Wnt/β-catenin signaling and provides neuroprotection in Alzheimer’s disease models.
Utilized HT22 cells and 5×FAD transgenic mouse model of Alzheimer's disease.
Conducted SuperTOPFlash, Co-IP, and Western blot assays to evaluate molecular mechanisms.
Performed MTT, BrdU, and immunofluorescence staining in HT22 cells.
Administered ISX9 intraperitoneally to different mouse groups for behavioral assessments.
Analyzed levels of Aβ peptides, Tau proteins, and neuroinflammatory factors.
ISX9 activated Wnt/β-catenin signaling through LRP6-AXIN1 interaction.
Increased hippocampal cell viability and proliferation in cell models.
Improved learning and memory in 5×FAD transgenic mice.
Reduced levels of Aβ peptides and Tau proteins in the AD model.
Modulated neuroinflammatory factors and upregulated BBB-related proteins.

Study Design

Type

RCT (n=40)

Blinding

investigator masked to group assignments

Randomization

random allocation using computerized random number generation tool

Multicenter

Structured PICO

Does ISX9 improve cognitive function and reduce Alzheimer's disease pathology in 5×FAD transgenic mice?

Population

6-month-old female 5×FAD transgenic mice (n=20) and wild-type littermates (n=20), average body weight 20 g, and mouse hippocampal neuronal HT22 cells.

Intervention

ISX9 20 mg/kg body weight intraperitoneally injected at an interval of one day for 2 months.

Comparator

Vehicle (10% DMSO and 90% corn oil) intraperitoneally injected.

Outcome

Cognitive and learning abilities (evaluated via Morris water maze, Novel object recognition, and Y-maze tests) and expression levels of Aβ peptides, Tau-related proteins, neuroinflammatory factors, and BBB-related proteins.surrogate

ISX9 demonstrates neuroprotective effects in an Alzheimer's disease mouse model by activating the Wnt/β-catenin signaling pathway, suggesting its potential as a therapeutic agent.

Limitations

Study conducted only in female 5×FAD transgenic mice limiting generalizability to males and humans.
Lack of precise quantitative data for primary behavioral outcomes in the manuscript provided.
Short duration of treatment (2 months) may not reflect long-term effects.
The study is preclinical (mouse model), so clinical efficacy and safety in humans remain unknown.

Abstract

Abstract Background Defective 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. Methods In 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. Results Our 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. Conclusion Our 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. Graphical Abstract

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