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Neurotoxicity Research

, Volume 35, Issue 2, pp 291–303 | Cite as

Development of a Human APOE Knock-in Mouse Model for Study of Cognitive Function After Cancer Chemotherapy

  • Andrew P. Speidell
  • Tamar Demby
  • Yichien Lee
  • Olga Rodriguez
  • Christopher Albanese
  • Jeanne Mandelblatt
  • G. William RebeckEmail author
ORIGINAL ARTICLE

Abstract

Cancer-related cognitive impairment in breast cancer patients exposed to multi-agent chemotherapy regimens is associated with the apolipoprotein E4 (APOE4) allele. However, it is difficult to determine the effects of specific agents on cognitive impairment in human studies. We describe the development of a human APOE knock-in congenic C57BL/6J mouse model to study cancer-related cognitive impairment. Female APOE3 and APOE4 homozygous mice were either left untreated or treated with the most commonly used breast cancer therapeutic agent, doxorubicin. APOE3 and APOE4 mice had similar behaviors in exploratory and anxiety assays, which were affected transiently by doxorubicin treatment. Spatial learning and memory were measured in a Barnes maze: after 4 days of training, control APOE3 and APOE4 mice were able to escape with similar latencies. In contrast, doxorubicin-treated APOE4 mice had markedly impaired learning compared to doxorubicin-treated APOE3 mice at all time points. Voxel-based morphometry of magnetic resonance images revealed that doxorubicin treatment caused significant changes in the cortex and hippocampus of in both APOE3 and APOE4 mouse brains, but the differences were significantly greater in the APOE4 brains. The results indicate that doxorubicin-exposed APOE4 mice recapitulate key aspects of human cancer-related cognitive impairment. These data support the usefulness of this novel preclinical model for future elucidation of the genetic and molecular interactions of APOE genotype with chemotherapy; this model can also allow extension to prospective studies of older mice to study these interactions in the context of aging.

Keywords

Cancer-related cognitive decline APOE Chemotherapy Preclinical model 

Notes

Acknowledgements

We would like to thank Idalia Cruz for her expertise with animal restraint and injection.

The authors would also like to acknowledge Charrell Sherman for her assistance with multiple behavioral assays. Finally, we thank Dr. Amanda DiBattista for sharing her Barnes maze protocols and suggestions with our research team.

Funding Information

This research was supported by the NIH R35 CA197289 and R01 CA129769 to JM, R01 NS100704 to GWR, T32NS041231 to APS, T32CA009686 to TD, and a Georgetown University Medical Center Toulmin Pilot Grant to GWR and JM. This study was also financially supported in part by the NIH grant P30 CA51008 to Lombardi Comprehensive Cancer Center for support of the Animal Model and Preclinical Imaging Shared Resources for animal handling and imaging,

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that that they have no conflicts of interest.

Statement on the Welfare of Animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of Georgetown University, where these studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeuroscienceGeorgetown UniversityWashingtonUSA
  2. 2.Department of OncologyGeorgetown UniversityWashingtonUSA

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