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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\n                    <jats:italic>\n                      Ptpro\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    female mice with doxorubicin (DOX) because\n                    <jats:italic>\n                      Ptpro\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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\n                    <jats:italic>\n                      Ptpro\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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\n                    <jats:italic>\n                      Ptpro\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.166306","type":"journal-article","created":{"date-parts":[[2023,7,23]],"date-time":"2023-07-23T14:01:07Z","timestamp":1690120867000},"source":"Crossref","is-referenced-by-count":29,"title":["Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment"],"prefix":"10.1172","volume":"8","author":[{"given":"Zhimeng","family":"Yao","sequence":"first","affiliation":[{"name":"Department of Urology Surgery, and"},{"name":"Department of General Surgery, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, China."},{"name":"Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, Guangdong, 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