Mapping Brain Lipid Architecture in Aging, LBD and T Cell Therapy using novel Imaging Mass Spectrometry

PROJECT SUMMARY Dementia with Lewy bodies (LBD) and Parkinson's disease (PD) are characterized pathologically by the presence of Lewy bodies, composed of misfolded alpha synuclein (α-syn) inclusions. These disorders are progressive, and result in the degeneration of dopaminergic neurons in multiple motor and non-motor basal

ganglia circuits. There are no known disease altering drugs, hence there is an unmet need for delivering viable treatments to slow down progression of LBDs. Furthermore, there is a growing body of literature suggesting the role that lipids play in LBD pathogenesis. We have developed a promising mRNA-based immunomodulatory

approach (ACT), which shows efficacy of reducing α-syn pathology burden in a preclinical model. We also show that ACT restores the lipidome to normal levels and hence visualizing the inter-brain distribution of lipids along with key enzymes involved in lipid metabolism would help comprehend their roles and alterations over time in

the aging and diseased brain. Systems biology approaches provide a holistic examination of interactions between the metabolome, and environment in an attempt to comprehend pathomechanisms involved in LBDs. Imaging mass spectrometry (IMS) is a new technology that has the ability to map a wide range of small molecules with high spatial resolution,

and the ability to quantify them, without a priori labeling, and hence can be harnessed to elucidate the role of the metabolome in driving neurodegeneration. Here we propose to generate a spatial atlas of the lipidome to identify lipid markers of disease progression in Aim 1, and assess lipid alterations resulting from ACT using MSI in Aim

2.