TY - JOUR
T1 - Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment
AU - Yao, Zhimeng
AU - Dong, Hongmei
AU - Zhu, Jianlin
AU - Du, Liang
AU - Luo, Yichen
AU - Liu, Qing
AU - Liu, Shixin
AU - Lin, Yusheng
AU - Wang, Lu
AU - Wang, Shuhong
AU - Wei, Wei
AU - Zhang, Keke
AU - Huang, Qingjun
AU - Yu, Xiaojun
AU - Zhao, Weijiang
AU - Xu, Haiyun
AU - Qiu, Xiaofu
AU - Pan, Yunlong
AU - Huang, Xingxu
AU - Yeung, Sai Ching Jim
AU - Zhang, Dianzheng
AU - Zhang, Hao
N1 - Publisher Copyright:
© 2023 American Society for Clinical Investigation. All rights reserved.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
KW - Aging
KW - Behavior
KW - Neurological disorders
KW - Phosphoprotein phosphatases
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U2 - 10.1172/jci.insight.166306
DO - 10.1172/jci.insight.166306
M3 - Article
C2 - 37485875
AN - SCOPUS:85165579578
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 14
M1 - e166306
ER -