2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Characterizing Doxorubicin-Induced Cognitive Impairment in APOE Mouse Model

How is chemotherapy-related cognitive impairment similar to Alzheimer’s?

Harshul Pandit, Ph.D.
Georgetown University
Washington, DC - United States

Background

The gene APOE provides instructions for making ApoE, a protein that helps carry fats throughout the brain and body. There are several variations of APOE, each of which has different impacts on Alzheimer’s risk. APOE-e4 is associated with increased risk for Alzheimer’s in some populations, APOE-e3 is neutral, and APOE-e2 is protective for some populations. 

Studies show that the APOE-e4 variation also leads to greater susceptibility to chemotherapy-related cognitive impairment (CRCI), a decline in memory following cancer treatment. Dr. Harshul Pandit and colleagues developed a genetically engineered mouse model to investigate how APOE variation interacts with the chemotherapy drug doxorubicin (DOX). In preliminary experiments, the research team found that when exposed to DOX, mice expressing the APOE-e3 gene showed similar brainchanges to mice expressing the APOE-e4 gene with no exposure to DOX. This suggests that the brains of APOE-e4 mice already show changes resembling the impact of DOX in the brains of APOE-e3 mice. These findings may indicate that Alzheimer’s and CRCI share common features and biological mechanisms.

Research Plan

Dr. Pandit and team believe that the APOE-e4 variation may be associated with pre-existing brain inflammation that predisposes individuals to damage and cognitive impairment after chemotherapy. Using genetically-engineered Alzheimer’s-like mice, the researchers will study the toxic brain microenvironment induced by DOX exposure and how this is impacted by APOE variation, sex, and aging. The research team will study biological changes following DOX treatment in male and female mice at different ages. The team will also characterize the biochemical and disease-related brain changes that occur in the mice after DOX treatment.

Impact

The findings may shed light on how an Alzheimer’s risk gene impacts chemotherapy-related cognitive impairment. The results may also contribute to the understanding of the biological mechanisms underlying cognitive impairment in Alzheimer’s and following cancer treatment.