Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment
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
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
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Research Article Aging

Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment

Abstract

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.

Authors

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

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Figure 5

Ptpro–/– female mice display more severe defects in dendritic spine morphogenesis and synaptic function in the hippocampi following DOX treatment.

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Ptpro–/– female mice display more severe defects in dendritic spine mor...
(A) Representative image of Golgi-stained hippocampal sections from Ptpro+/+ mice treated with DOX. Scale bar: 500 μm. DG, dentate gyrus. (B) Representative images and drawings of Golgi-stained hippocampal CA3 pyramidal neurons from Ptpro+/+ (left panel) and Ptpro–/– mice (right panel). Scale bar: 50 μm. (C and D) Quantification of the total dendritic length and primary dendrites of CA3 pyramidal neurons from the Ptpro+/+ and Ptpro–/– mice. n = 4 per genotype. At least 10 cells were analyzed per mouse. (E) Sholl’s analysis of the complexity of CA3 pyramidal neurons the Ptpro+/+ and Ptpro–/– mice. n = 4 per genotype. At least 10 cells were analyzed per mouse. (F) Representative photomicroscopy images of Golgi-stained dendrites of CA3 pyramidal neurons from the Ptpro+/+ and Ptpro–/– mice. Scale bars: 5 μm. (G) Quantitative analysis of spine densities in CA3 pyramidal neurons from the Ptpro+/+ and Ptpro–/– mice. n = 4 per genotype; an average of 5 dendrites of CA3 pyramidal neurons were analyzed per mouse. (H) Representative immunofluorescence images of synaptophysin (Syp) and PSD95 in hippocampal CA3 sections from Ptpro+/+ and Ptpro–/– mice. Scale bars: 100 μm. (I) Quantification analysis of the average fluorescence intensity of Syp in hippocampal CA3 sections from Ptpro+/+ and Ptpro–/– mice. n = 5 per genotype. (J) Quantification analysis of the average fluorescence intensity of PSD95 in hippocampal CA3 sections from Ptpro+/+ and Ptpro–/– mice. n = 5 per genotype. (K) Immunoblotting of Syp and PSD95 in the hippocampi of Ptpro+/+ and Ptpro–/– mice. These results are representative of 3 independent experiments. Error bars: SEM. **P < 0.01, ***P < 0.001 by 2-sided Student’s t test (C, D, G, I, and J) or 2-way ANOVA followed by Bonferroni’s multiple-comparison test (E).