Zebrafish Spatial Neurolipidomics Investigation of Neuroprotection in Chemotherapy-induced Cognitive Decline

Chemotherapy-induced cognitive decline, or “chemobrain”, is a debilitating condition experienced by an average 45% of cancer patients. Symptoms include learning and memory issues, motor deficits, poor mental health, and other physiological impairments – and in some cases, effects can last for years afterward. Despite the known prevalence of chemobrain, its mechanism is poorly understood, and current management strategies are extremely limited without a single approved drug. Our group has recently demonstrated the neuroprotective potential of L-carnosine (CAR) in a zebrafish model of chemobrain. CAR treatment before and during chemotherapy significantly reduced behavioral and neurochemical symptoms. In humans and our model, significant changes in lipid biosynthesis have been observed – lipid localization and accumulation have long been linked to neurodegeneration, but the exact spatial distribution and the extent of rescue have yet to be explored.

In this work, we utilized mass spectrometry-based lipidomics to investigate the distribution and quantitation of several classes of lipids implicated in dementia such as cholesterol, ceramides, and phosphatidylinositols. Current literature for zebrafish lipidomics is limited to studies of whole brain homogenate which cannot discern the native locations of each lipid species. This study aims to shed light on the role of lipids in chemobrain pathology and progression, as well as the mitigating effects of CAR and its mechanism. Our study provides the first methods and report of MALDI-MSI in zebrafish brains, clarifies the multimodal role of CAR neuroprotection, and identifies key areas of lipid metabolic dysfunction in chemobrain. In this presentation, we will discuss the broad applicability of these methods, describe exciting functional and metabolic insights into CAR’s bioactivity, and explore the downstream implications for chemobrain management.