Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment
Chemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-07-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.166306 |
| _version_ | 1797634323044630528 |
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| author | Zhimeng Yao Hongmei Dong Jianlin Zhu Liang Du Yichen Luo Qing Liu Shixin Liu Yusheng Lin Lu Wang Shuhong Wang Wei Wei Keke Zhang Qingjun Huang Xiaojun Yu Weijiang Zhao Haiyun Xu Xiaofu Qiu Yunlong Pan Xingxu Huang Sai-Ching Jim Yeung Dianzheng Zhang Hao Zhang |
| author_facet | Zhimeng Yao Hongmei Dong Jianlin Zhu Liang Du Yichen Luo Qing Liu Shixin Liu Yusheng Lin Lu Wang Shuhong Wang Wei Wei Keke Zhang Qingjun Huang Xiaojun Yu Weijiang Zhao Haiyun Xu Xiaofu Qiu Yunlong Pan Xingxu Huang Sai-Ching Jim Yeung Dianzheng Zhang Hao Zhang |
| author_sort | Zhimeng Yao |
| collection | DOAJ |
| description | Chemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro–/– female mice with doxorubicin (DOX) because Ptpro–/– female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro–/– female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro–/– female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI. |
| first_indexed | 2024-03-11T12:06:01Z |
| format | Article |
| id | doaj.art-c35e5fe023e7491690445e9e104c3da6 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:01Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-c35e5fe023e7491690445e9e104c3da62023-11-07T16:25:54ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-07-01814Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairmentZhimeng YaoHongmei DongJianlin ZhuLiang DuYichen LuoQing LiuShixin LiuYusheng LinLu WangShuhong WangWei WeiKeke ZhangQingjun HuangXiaojun YuWeijiang ZhaoHaiyun XuXiaofu QiuYunlong PanXingxu HuangSai-Ching Jim YeungDianzheng ZhangHao ZhangChemotherapy-related cognitive impairment (CRCI) or “chemo brain” is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro–/– female mice with doxorubicin (DOX) because Ptpro–/– female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro–/– female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro–/– female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.https://doi.org/10.1172/jci.insight.166306Aging |
| spellingShingle | Zhimeng Yao Hongmei Dong Jianlin Zhu Liang Du Yichen Luo Qing Liu Shixin Liu Yusheng Lin Lu Wang Shuhong Wang Wei Wei Keke Zhang Qingjun Huang Xiaojun Yu Weijiang Zhao Haiyun Xu Xiaofu Qiu Yunlong Pan Xingxu Huang Sai-Ching Jim Yeung Dianzheng Zhang Hao Zhang Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment JCI Insight Aging |
| title | Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment |
| title_full | Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment |
| title_fullStr | Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment |
| title_full_unstemmed | Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment |
| title_short | Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment |
| title_sort | age related decline in hippocampal tyrosine phosphatase ptpro is a mechanistic factor in chemotherapy related cognitive impairment |
| topic | Aging |
| url | https://doi.org/10.1172/jci.insight.166306 |
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