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 four 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 pre-clinical 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.
The purpose of this study was to establish the effects of Apolipoprotein E (APOE) genotype on cognitive function following doxorubicin treatment in a mouse model. Chemotherapy treatment can lead to cognitive impairment in cancer survivors, and, in older breast cancer survivors, APOE4 carriers have been shown to have higher risk for these impairments. Though APOE4 genotype is known as the strongest genetic risk factor for late-onset Alzheimer’s Disease compared to the APOE2 and APOE3 alleles, its effects on cognitive outcomes following treatment with common breast cancer chemotherapeutics are not yet well characterized. One year old female mice with targeted replacement of human APOE3 or APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or saline. Five weeks following treatment, spatial learning and memory was tested using the Barnes Maze. In APOE3 mice, doxorubicin treatment left spatial learning and memory intact. In APOE4 mice, doxorubicin treatment lead to impairment in spatial learning over the four days of training. This represents a promising model for studying the mechanisms behind cognitive impairment following doxorubicin treatment in a genetically vulnerable population. Citation Format: Tamar C. Demby, Yichien Lee, Olga Rodriguez, Christopher Albanese, Jeanne Mandelblatt, G. William Rebeck. A mouse model of APOE to define effects of doxorubicin on cognition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 667.
OBJECTIVES/SPECIFIC AIMS: Chemotherapy-related cognitive impairment (CRCI) affects 15-35% of breast cancer survivors and constitutes a significant challenge for survivor quality of life. Among older breast cancer survivors who received chemotherapy treatment, carriers of at least one ɛ4 allele of the APOE gene, which encodes apolipoprotein E, are at higher risk for developing CRCI than non-carriers. APOE4 is well characterized as the strongest genetic risk factor for Alzheimer’s disease, but how it contributes to CRCI is not yet understood, and no animal models of APOE genotype and CRCI have yet been established. To better understand how APOE4 acts as a risk factor for CRCI, we used APOE targeted replacement (TR) mice to develop a model of its effects on cognition following treatment with doxorubicin, a chemotherapy drug commonly used in breast cancer treatment. METHODS/STUDY POPULATION: Twelve-to-thirteen month old APOE3 and APOE4 targeted replacement mice expressing human APOE3 or human APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or equivolume saline given via two IP injections spaced one week apart. One week post-treatment, mice were tested using Open Field and Elevated Zero apparatuses to assess baseline locomotive activity and anxiety and exploratory behaviors. Five weeks post-treatment, mice were assessed using the Barnes Maze over four days of training trials and one 72 hour memory probe. RESULTS/ANTICIPATED RESULTS: We found no differences in Open Field and Elevated Zero behavior, indicating limited influence of doxorubicin treatment on locomotive and anxiety behaviors in both genotypes. During Barnes Maze training, APOE4 mice treated with doxorubicin showed increased latency compared to untreated APOE4 mice as well as treated and untreated APOE3 mice, indicating deficiencies in spatial learning. In APOE3 mice, no differences in performance were seen between doxorubicin-treated and untreated mice (n = 15-16/group, p <.0001). DISCUSSION/SIGNIFICANCE OF IMPACT: These results indicate that APOE4 targeted replacement mice have specific cognitive vulnerabilities to doxorubicin treatment that can be reliably detected using the Barnes Maze assessment. Future directions include experiments to determine how other chemotherapy drugs or drug combinations impact cognition of APOE4 mice. Ultimately this model may be used to assess preventive measures or therapies for CRCI in the vulnerable APOE4 carrier population with the ability to validate cognitive impacts of these interventions.
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