Imaging Mass Spectrometry-Based Metabolomic Analysis of the Alzheimer's Brain

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IMAGING MASS SPECTROMETRY-BASED METABOLOMIC ANALYSIS OF THE ALZHEIMER'S BRAIN PROJECT SUMMARY Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Although multiple genes and their mutations linked to AD pathogenesis have been reported, the pathogenic mechanisms of AD still remain elusive. The focus of the majority of AD research has been targeted towards the selective loss of specific neuronal populations. Still, less effort has been spent in understanding reactive astrocytes, a feature common to injury and disease in the aged brain. Recently, we described a subtype of reactive astrocytes that are observed in various human neurodegenerative diseases, including AD and Parkinson's disease (PD). Activation of microglia leads to the conversion of astrocytes into neurotoxic reactive astrocytes via secretion of IL-1, TNF, and C1q. Blocking microglia activation with the drug, NLY01 prevented astrocyte conversion to reactive astrocytes providing neuroprotection. The conversion of resting microglia and astrocytes to reactive ones is deeply related to changes in energy metabolism and lipid composition in the cell. Resting microglia mainly rely on oxidative phosphorylation for energy production. When microglia metabolism converts from oxidative phosphorylation to glycolysis, microglia are activated. This change subsequently converts resting astrocytes to reactive ones ramping up their glucose consumption. Long-chain saturated lipids in APOE and APOJ secreted by astrocytes also have been reported to show neurotoxicity. Therefore, understanding metabolomic changes in microglia, astrocytes, and neurons during the course of neurodegeneration is likely to provide a deeper understanding of AD pathogenesis. Imaging mass spectrometry-based metabolomic analysis will provide a view of cell-type and region-specific metabolomic changes in the brain. To study metabolomic changes in a cell-type-specific manner, we propose three specific aims. (Aim 1) We will examine region- and cell-type-specific metabolomic changes in the microglia-astrocyte-neuron axis in the brain of mice overexpressing amyloid β and in response to pathologic tau. (AIM 2) We will examine region- and cell-type- specific metabolomic changes in control and AD human post-mortem brains. (Aim 3) We will compare region- and cell-type-specific brain metabolomic changes of mice overexpressing amyloid β and in response to pathologic tau with the ones lacking microglial activation by the treatment with PLX3397 or NLY01. The completion of these aims will provide a better understanding of cell-type metabolome dynamics during aging and neurodegeneration mediated by overexpressed amyloid β and pathologic-tau injection. The novel information acquired in this study will provide indispensable insights into cell-type-specific AD pathogenic mechanisms and offer new opportunities to develop new AD treatments targeting microglia and astrocytes. Furthermore, this strategy can be expanded to study the pathogenesis of other brain diseases. 1