The APOE4 Mouse as a Model of Chemotherapy-induced Cognitive Impairments and Senescence

Abstract

Cancer-related cognitive impairment (CRCI) occurs in 15-35% of breast cancer survivors and represents a major quality of life concern. CRCI has been linked to the APOE4 genotype, the strongest genetic risk factor for Alzheimer’s disease. In this project, I used APOE targeted (APOE-TR) mice to test whether the relationship between APOE4 and CRCI can be demonstrated in a mouse model, to identify associations of chemotherapy with behavioral correlates of cognition, and to characterize mechanisms of damage to the central nervous system (CNS) by chemotherapy. To assess cognitive function, 12-month-old female APOE3 and APOE4 mice were exposed to either doxorubicin (10 mg/kg) or saline. In the Barnes maze assay conducted six weeks post-exposure, APOE3 mice did not exhibit impairment in spatial learning after doxorubicin treatment, but APOE4 mice demonstrated significant impairments in both the initial identification of the escape hole and the latency to full escape. To directly study how doxorubicin exposure affects the brain to cause cognitive impairment in APOE4 mice, I conducted an acute time course of doxorubicin using six-month-old female APOE3 and APOE4 mice exposed to doxorubicin and euthanized one, three, seven, or 21 days after treatment, or saline control. A neuroinflammation gene expression panel with RT-qPCR validation identified transcriptional upregulation of senescence genes Cdkn1a, Egr1, and Gadd45α at 21 days post-doxorubicin exposure in APOE4 but not APOE3 mice. This finding represents the first direct evidence of senescence as a mechanism underlying CRCI in the vulnerable APOE4 genotype context. Overall, this project demonstrates cognitive impairments in aged APOE4 mice after doxorubicin treatment, identifies a senescence-related transcriptional signature induced in APOE4 mice after doxorubicin, and establishes this system as a novel and powerful model to study mechanisms of and interventions for CRCI.