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 9

Region-specific restoration of hippocampal PTPRO in Ptpro–/– female mice treated with DOX ameliorates synaptic function.

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Region-specific restoration of hippocampal PTPRO in Ptpro–/– female mice...
(A) Representative images and drawings of Golgi-stained hippocampal CA3 pyramidal neurons in each group. Scale bar: 50 μm. (B and C) Quantification of the total dendritic length and primary dendrites of CA3 pyramidal neurons. n = 4 per group. (D) Sholl’s analysis of the complexity of CA3 pyramidal neurons. n = 4 per group. *Ptpro–/–-LVCon vs. Ptpro–/–-LVPtpro. (E) Representative photomicroscopy images of Golgi-stained dendrites of CA3 pyramidal neurons. Scale bars: 5 μm. (F) Quantitative analysis of spine densities in CA3 pyramidal neurons. n = 6 per group. (G) Time course of fEPSP measurements were recorded in the hippocampal CA1 region before and after 100-Hz stimulation in the Schaffer collateral region. Normalized fEPSP slopes were plotted every 1 minute for each group. HFS, high-frequency stimulation. (H) The averaged fEPSPs recorded 56–60 minutes after induction of LTP. n = 6 slices from 4–6 mice. (I) Representative immunofluorescence images of Syp and PSD95 in hippocampal CA3 sections. Scale bars: 200 μm. (J) Quantification analysis of the average fluorescence intensity of Syp in hippocampal CA3 sections. n = 5 per group. (K) Quantification analysis of the average fluorescence intensity of PSD95 in hippocampal CA3 sections. n = 5 per group. (L) Immunoblotting of Syp and PSD95 in the hippocampi of mice. n = 3 per group. These results are representative of 3 independent experiments. Error bars: SEM. NS, not significant; *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA followed by a Tukey-Kramer post hoc test (B, C, F, H, J, and K) or 3-way ANOVA followed by Tukey’s multiple-comparison test (D).