Abstract 7452: ApoE genotype influences susceptibility to doxorubicin-induced cognitive impairment in juvenile rats

Abstract

Abstract Many pediatric cancer survivors experience chemotherapy-induced cognitive impairment (CICI), which negatively impacts the quality of life. Despite extensive research into the multifactorial causes of CICI, there are no FDA approved drugs available to prevent it and the interpatient variability in susceptibility to CICI is not well understood. Among pediatric cancer survivors, those with the E4 allele of Apolipoprotein E (ApoE) are more likely to exhibit cognitive dysfunction than those with the more prevalent ApoE3 allele, suggesting the ApoE4 allele increases susceptibility to CICI. To mimic a curative pediatric treatment regimen, in our experimental model, five-week-old rats homozygous for either human ApoE3 or ApoE4 allele were treated with doxorubicin (DOXO) (2mg/kg/week for 4 weeks) or saline. ApoE4 rats were more likely than ApoE3 rats to exhibit DOXO-induced impairments in visual memory. However, there was no difference between ApoE3 and ApoE4 rats in sensitivity to DOXO-induced spatial memory impairments. Contrast-enhanced magnetic resonance imaging (MRI) was done to evaluate the blood-brain barrier (BBB) integrity because of literature suggesting that the ApoE4 allele contributes to BBB weakness. However, no significant difference was observed in the BBB integrity between ApoE3 and ApoE4 rats. To delve deeper into the neuropathological basis of DOXO-induced cognitive impairment on the ApoE4 allele, ongoing experiments involve immunohistochemical analyses targeting neurogenic changes in neural stem cell proliferation (DCX), neuronal maturation (Syn and PSD95), as well as glial differentiation (Iba1 and GFAP) in brain regions including hippocampus (dentate gyrus) and cortex. Additionally, to determine the effect of DOXO treatment on ApoE4, we are investigating the role of mitogen-activated protein kinase (MAPK) signaling pathways within brain regions pertinent to memory and recognition. In summary, ApoE genotype contributes to differential susceptibility to CICI. Citation Format: Chadni Patel, Jeremy Willekens, Frank Diglio, Peter Cole. ApoE genotype influences susceptibility to doxorubicin-induced cognitive impairment in juvenile rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7452.