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Background <p>Growing 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.</p> Methods <p>Wnt 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 <i>APOE</i> ε4/ε4 genotype or <i>MAPT</i> p.P301L mutation.</p> Results <p>We 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 <i>APOE</i> ε4/ε4 genotype or <i>MAPT</i> 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 <i>NEUROD1</i>, <i>CACNA1G</i>, <i>NRGN, NRTN, SLC7A10 and OMG</i>.</p> Conclusion <p>Our findings suggest that CI-994 can be repurposed as a novel therapeutic agent for AD therapy.</p>

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CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Wenyan Lu,
  • Keiji Kawatani,
  • Yingxue Ren,
  • Toshihiko Nambara,
  • Lin Jia,
  • Suren Jeevaratnam,
  • Eunmi Lee,
  • Paula Rodriguez Martinez,
  • Taha Izhar,
  • Ni Wang,
  • Ana-Caroline Raulin,
  • Zbigniew K. Wszolek,
  • Guojun Bu,
  • Takahisa Kanekiyo,
  • Yonghe Li

摘要

Background

Growing 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.

Methods

Wnt 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.

Results

We 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.

Conclusion

Our findings suggest that CI-994 can be repurposed as a novel therapeutic agent for AD therapy.