Supplement: (PQ9) A Redox-Mediated Mechanism of Chemotherapy-Induced Cognitive Impairment

This application is a supplemental request, under NOT-AG-18-008, for our NCI-funded, Multiple PI grant, 1R01 CA217934-01, “(PQ9) A Redox-Mediated Mechanism of Chemotherapy-Induced Cognitive Impairment.” Key aspects of this MPI R01 grant are that, following systemic administration of BBB-impermeable, redox-cycling, and ROS-producing doxorubicin (Dox) and the BCL2 target drug Venetoclax, the injured tissues release extracellular vesicles (EVs) containing 4-hydroxynonenal (HNE)-adducted proteins and subsequently activate immune cells to generate the pro-inflammatory cytokine, TNFá to cause elevated brain oxidative stress and chemotherapy-induced cognitive impairment (CICI) in animal models. The UK Sanders-Brown Center on Aging serves and follows a cohort of community-based adults who exhibit the full spectrum of cognition, from intact cognition to dementia. The cohort continuously enrolls a group of about 500 cognitively intact participants. These participants undergo annual cognitive testing, provide plasma/serum samples, and often also have data from imaging modalities. ADC participants agree to donate their brains at the time of death. Two hundred and sixty-one out of 767 ADC participants for whom there are autopsy data are cancer suvivors, who had a known history of cancer and had been treated prior to death due to AD, with chemotherapeutic agents and/or radiation. Importantly, serum is banked by our ADC core for approximately 60% of these individuals. Collectively, the assembled resources and expertise of the team provide an ideal experimental context to study the impact of cancer, chemotherapeutic modalities, and serum analytes in terms of association with both cognitive impairment and neuropathologic observations. Given that Aims 2 and 3 of our MPI R01 from NCI deal with EVs from murine models of CICI, and given the strength of our ADC cohort with the many well-characterized particpants, who were followed for more than 10 years from a cognitively normal state, we will test the hypothesis that plasma-resident, neuronal-derived EVs from autopsied ADC participants who were treated with chemotherapy and/or radiation contain considerably more and unique HNE-bound neuronal proteins than do plasma-resident EVs from neurons of patients who died with AD but with no cancer. We will isolate plasma EVs from 50 cancer survivors with AD and from 50 non-cancer AD persons and compare their 4HNE adducted protein content. Samples with the most significant differences in the 4HNE adducted proteins between AD with and without cancer will be further evaluated for their protein content and function by redox proteomics and immune activation approaches. We propose that redox proteomics will identify that some of these neuronal-derived EVs contain novel target proteins that facilitate future new drug development. The success of our published work on drug-derived EVs and the track record of the UK-ADC demonstrate that we have a strong likelihood of successfully testing our novel hypotheses that will tie cognitive dysfunction associated with cancer therapy to molecular processes that are major components of dementia.