Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis

<p>One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test and novel object/place recognition test. Long-term CICD was associated with a decreased expression of the postsynaptic protein PSD95, but no decrease in the presynaptic protein synaptophysin, in the hippocampus. I did not detect a significant decrease in mitochondrial function or morphology in brain synaptosomes, myelination in the cingulate cortex using Black Gold II staining, or changes in astrocyte reactivity as assessed by anti-GFAP immunofluorescence staining. Using advanced imaging techniques and single-nucleus RNA sequencing, I demonstrate that doxorubicin-induced changes are associated with decreased microglial ramification and alterations in the microglia transcriptome that suggest a neurodegenerative microglia phenotype closely resembling stage 1 disease-associated microglia (DAMs). HDAC6 inhibition completely reversed these doxorubicin-induced alterations, indicating a restoration of microglial homeostasis. These results suggest that a stage 1 DAM-like microglia phenotype and decreased postsynaptic integrity contribute to long-term CICD. Moreover, HDAC6 inhibition shows promise as an efficacious pharmaceutical intervention to alleviate CICD and improve quality of life of breast cancer survivors.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• McAlpin, Blake
• <p><strong>0000-0002-6539-8406</strong></p>

Contributors dc:contributor

• Cobi J. Heijnen, Ph.D.
• M. Neal Waxham, Ph.D.
• Robert Dantzer, D.V.M., Ph.D.

• chemotherapy-induced cognitive dysfunction
• chemobrain
• HDAC6 inhibition
• microglia
• single-nucleus RNA sequencing
• chemofog
• snRNA-seq
• synaptic integrity
• PSD95
• Medical Neurobiology
• Medicine and Health Sciences
• Neurosciences
• Oncology
• Other Chemicals and Drugs
• Other Neuroscience and Neurobiology
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1160

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2213