Imaging brain metabolism in a mouse model of Huntington's disease

Abstract

Introduction: Huntington's disease (HD) is a neurodegenerative disease, whose key pathological signature is the formation of intracellular inclusions. However, the exact role of inclusions in driving HD pathology remains to be clearly understood. Our lab has previously shown that the formation of huntingtin inclusions correlates with neuroblastoma cells becoming functionally quiescent and undergoing a slow death by necrosis. We hypothesize that inclusion formation establishes cellular quiescence in vivo. Our goal is to assess the extent to which neurons in vivo are metabolically quiescent and how this relates to the presence of inclusions in a transgenic mouse model (R6/1) of HD.Methods: We have studied the metabolic turnover of neuronal membrane lipids by feeding wild-type (WT) and HD mice with deuterated water at asymptomatic, pre-symptomatic &fully symptomatic ages of the disease. The left hemisphere of the brain was used for determining the spatial distribution and the abundance of neuronal lipids using MALDI-TOF imaging mass spectrometry (MALDI-IMS), while the right hemisphere was reserved for cross-validation using Liquid-Chromatography mass spectrometry (LC-MS). Results: Our data points towards alterations in neuronal lipids that play a critical role in neurotransmission, synaptic plasticity, myelination, and Endoplasmic reticulum (ER)- stress, thus providing lipid correlates for hippocampal-dependent cognitive deficits observed in HD pathology. Moreover, we found a remodeling of lipid synthesis in hippocampal areas that are densely populated by inclusions, detected using EM48-immunohistochemistry. We have also developed a novel bioinformatics tool to study in vivo kinetics using stable isotope labelling (Deuterium) coupled with a spatial metabolic approach.Conclusion: Collectively, this data reveals age-specific changes in brain lipids, providing mechanistic insights into the progressive changes observed in HD. Accelerated lipid synthesis observed in asymptomatic HD mice, hints at its possible role as an adaptive stress response to cope with ER-stress, thus providing an early biomarker for identification of HD