Using a murine model to explore the impact of sex and APOE4 on cisplatin-induced cognitive impairment

Abstract

Chemotherapy-induced cognitive impairment (CICI) is reported in over 35% of cancer survivors. Understanding risk factors for the development of CICI may provide insight into mechanisms and treatment. Being female and carrying the E4 allele of the APOE gene are risk factors for late-onset Alzheimer's disease, and there is emerging evidence that they may also confer risk for CICI. We sought to investigate these factors in a middle-aged (8-9 months) murine model of CICI. We used a 2 (+/- cisplatin) x 2 (male/female) x 2 (wild-type/APOE4 transgenic) factorial design in which cisplatin, or an equal volume of saline vehicle, was administered at 2.3 mg/kg/day for 5 days for 2 rounds separated by a 5-day rest. Behavioral tests of cognition and activity were evaluated one month after treatment completion followed by tissue collection. Male mice exhibited more severe weight loss following cisplatin, irrespective of genotype. Cisplatin was also associated with reduced open-field and nest building activity for both sexes and genotypes. In the puzzle box task, cisplatin treatment reduced performance in the task with indication that sex and genotype trial dependently modulated performance. In the novel object task, male mice of both genotypes showed cisplatin-induced deficits. In analyzing tissue, we did not note significant cisplatin-induced neuroinflammatory processes. We did observe an effect of cisplatin on brain Bdnf mRNA expression that varied by brain region, sex, and genotype. Within the hippocampus, cisplatin reduced Bdnf in male mice but mildly elevated it within female mice; within the frontal cortex, Bdnf expression was reduced by cisplatin in both sexes but more severely in APOE4 mice. Overall, our data provide evidence that both sex and genotype may modulate the effect of cisplatin on the brain and on cognitive performance.

Keywords: APOE; Chemotherapy; Cognition; Neurodegeneration; Neuroinflammation; Premature aging; Sex differences.