Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathway
Alzheimer’s disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenes...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823001925 |
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| author | Minguen Yoon Heejene Kim Heewon Shin HeeYang Lee Min-Jeong Kang Sung-Hye Park Gyoonhee Han YoungSoo Kim Kang-Yell Choi |
| author_facet | Minguen Yoon Heejene Kim Heewon Shin HeeYang Lee Min-Jeong Kang Sung-Hye Park Gyoonhee Han YoungSoo Kim Kang-Yell Choi |
| author_sort | Minguen Yoon |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenesis in AD. Increasing evidence suggests that the suppression of the Wnt/β-catenin signaling pathway plays substantial roles in AD progression. However, the underlying mechanism for the suppression of Wnt/β-catenin pathway associated with AD pathogenesis remains unexplored. In this study, we identified that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed in the tissues of AD patients and 5xFAD transgenic mice paired with the suppression of Wnt/β-catenin pathway and its target genes related to AD. The level of CXXC5 was upregulated, upon aging of 5xFAD mice. AD characteristics including cognitive deficits, amyloid-β (Aβ) plaques, neuronal inflammation, and age-dependent increment of AD-related markers were rescued in Cxxc5-/-/5xFAD mice. 5-methoxyindirubin-3'-oxime (KY19334), a small molecule that restores the suppressed Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, significantly improved the overall pathogenic phenotypes of 5xFAD mice. Collectively, our findings revealed that CXXC5 plays a key role in AD pathogenesis and suggest inhibition of CXXC5-Dvl interaction as a new therapeutic approach for AD. |
| first_indexed | 2024-03-12T14:21:54Z |
| format | Article |
| id | doaj.art-e9a6c1e3fcbe4d8fb99c697192e34fbb |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-12T14:21:54Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-e9a6c1e3fcbe4d8fb99c697192e34fbb2023-08-19T04:31:27ZengElsevierPharmacological Research1096-11862023-08-01194106836Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathwayMinguen Yoon0Heejene Kim1Heewon Shin2HeeYang Lee3Min-Jeong Kang4Sung-Hye Park5Gyoonhee Han6YoungSoo Kim7Kang-Yell Choi8Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of KoreaDepartment of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Republic of KoreaDepartment of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Republic of KoreaCK Regeon Inc, Seoul 03722, Republic of KoreaDepartment of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of KoreaDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of KoreaDepartment of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea; Corresponding author.Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; CK Regeon Inc, Seoul 03722, Republic of Korea; Corresponding author at: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.Alzheimer’s disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenesis in AD. Increasing evidence suggests that the suppression of the Wnt/β-catenin signaling pathway plays substantial roles in AD progression. However, the underlying mechanism for the suppression of Wnt/β-catenin pathway associated with AD pathogenesis remains unexplored. In this study, we identified that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed in the tissues of AD patients and 5xFAD transgenic mice paired with the suppression of Wnt/β-catenin pathway and its target genes related to AD. The level of CXXC5 was upregulated, upon aging of 5xFAD mice. AD characteristics including cognitive deficits, amyloid-β (Aβ) plaques, neuronal inflammation, and age-dependent increment of AD-related markers were rescued in Cxxc5-/-/5xFAD mice. 5-methoxyindirubin-3'-oxime (KY19334), a small molecule that restores the suppressed Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, significantly improved the overall pathogenic phenotypes of 5xFAD mice. Collectively, our findings revealed that CXXC5 plays a key role in AD pathogenesis and suggest inhibition of CXXC5-Dvl interaction as a new therapeutic approach for AD.http://www.sciencedirect.com/science/article/pii/S1043661823001925Alzheimer’s disease5xFADWnt/β-catenin signaling pathwayCXXC5Cxxc5-/-/5xFAD miceCXXC5-Dvl protein-protein interaction |
| spellingShingle | Minguen Yoon Heejene Kim Heewon Shin HeeYang Lee Min-Jeong Kang Sung-Hye Park Gyoonhee Han YoungSoo Kim Kang-Yell Choi Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathway Pharmacological Research Alzheimer’s disease 5xFAD Wnt/β-catenin signaling pathway CXXC5 Cxxc5-/-/5xFAD mice CXXC5-Dvl protein-protein interaction |
| title | Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathway |
| title_full | Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathway |
| title_fullStr | Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathway |
| title_full_unstemmed | Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathway |
| title_short | Inhibition of CXXC5 function rescues Alzheimer’s disease phenotypes by restoring Wnt/β-catenin signaling pathway |
| title_sort | inhibition of cxxc5 function rescues alzheimer s disease phenotypes by restoring wnt β catenin signaling pathway |
| topic | Alzheimer’s disease 5xFAD Wnt/β-catenin signaling pathway CXXC5 Cxxc5-/-/5xFAD mice CXXC5-Dvl protein-protein interaction |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823001925 |
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