CNSC-14. CARBOPLATIN IMPAIRS OPTIC NERVE MYELINATION IN NEUROFIBROMATOSIS TYPE 1 (NF1) BY REDUCING CHOLESTEROL LEVELS AND INDUCING OLIGODENDROCYTE LOSS

Abstract BACKGROUND Vision impairment is a major concern for patients with Neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG). Carboplatin-based chemotherapy is commonly used to treat NF1-OPG, but it does not consistently improve optic pathway neuron function. Chemotherapy is associated with changes in white matter microstructure of NF1-OPG patients; therefore, it is critical to understand the impact of chemotherapy on optic pathway oligodendroglial integrity in NF1. This study investigates the tumor-independent effects of carboplatin on the oligodendroglial lineage and optic nerve myelination in NF1, while testing strategies to mitigate chemotherapy-induced ocular toxicity. METHODS Nf1-heterozygous mice received carboplatin or vehicle, and the optic nerves and/or eyes were collected for immunohistochemistry, transmission electron microscopy, RNA sequencing, and/or biochemical studies. RESULTS We found that a clinically relevant dose of carboplatin induces oligodendrocyte loss and impairs myelin sheaths in the optic nerve of Nf1-heterozygous mice. This effect can be counteracted by administering clemastine, a compound that promotes myelination. Additionally, carboplatin increases the density of microglia/macrophages (Iba1+ cells), which negatively correlates with oligodendrocyte density in the optic nerve. Utilizing PLX5622 to decrease microglia/macrophage numbers alleviated the carboplatin-induced oligodendrocyte loss. Using transcriptomics to identify the underlying molecular contributors, we found that carboplatin downregulates genes essential for cholesterol biosynthesis. This carboplatin-induced decrease in optic nerve cholesterol was confirmed using liquid chromatography mass spectrometry. Notably, providing dietary cholesterol to the carboplatin-exposed Nf1-heterozygous mice restored the loss of oligodendrocytes. CONCLUSIONS Our findings revealed that carboplatin induces optic nerve oligodendroglial toxicity in the context of NF1, which can be rescued by clemastine, PLX5622, or dietary cholesterol.