ArticleAlzheimer's research & therapy2026
CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease.
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.
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1 citing paper in PubMed.
- Discovery of a CI-994 derivative as a dual modulator of class I HDACs and Wnt/β- catenin signaling for Alzheimer's disease therapy.bioRxiv : the preprint server for biology · 2026Article
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Abstract
backgroundGrowing evidence supports that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in Alzheimer’s disease (AD), and that HDACs have been highlighted as an attractive class of targets for AD therapy. Moreover, restoring Wnt/β-catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy. CI-994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI-994 can cross the blood–brain barrier and is a cognitive enhancer.
methodsWnt activity was initially examined by Wnt reporter activity assay in Wnt3A-expression HEK293 cells, and profiling HDAC inhibition was performed against 10 individual HDACs. Activities of CI-994 on class I HDACs and Wnt/β-catenin signaling were further tested in HEK293 cells, LRP6-expressing HT1080 cells and neuronal SH-SY5Y cells. The therapeutic effects of CI-994 were examined in patient-specific iPSC-derived neurons and cerebral organoids carrying APOE ε4/ε4 genotype or MAPT p.P301L mutation.
resultsWe herein report that CI-994 is not only a potent class I HDAC inhibitor but also an activator of Wnt/β-catenin signaling. Mechanistically, activation of Wnt/β-catenin signaling by CI-994 is associated with stabilizing Wnt co-receptor LRP6 protein and modulating HDAC activity. Importantly, CI-994 significantly increases histone acetylation, activates Wnt/β-catenin signaling, and decreases tau phosphorylation in patient-specific iPSC-derived cerebral organoids carrying APOE ε4/ε4 genotype or MAPT p.P301L mutation. Moreover, studies with the specific Wnt inhibitor LGK974 demonstrate that activation of Wnt/β-catenin signaling contributes to CI-994-induced the inhibition of tau phosphorylation in the iPSC-derived cerebral organoids. Additionally, CI-994 increases synaptic protein levels, enhances spontaneous synaptic firing and network formation and decreases tau phosphorylation in iPSC-derived neurons. Finally, RNA sequencing, combined with RT-qPCR validation, of the iPSC-derived cerebral organoids reveals that CI-994 significantly regulates genes associated with synapse plasticity and cognitive function including NEUROD1, CACNA1G, NRGN, NRTN, SLC7A10 and OMG.
conclusionOur findings suggest that CI-994 can be repurposed as a novel therapeutic agent for AD therapy.
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