Spatial dysregulation of the lipidome in Alzheimers disease human and mouse brain

点击翻译按钮获取中文摘要

Whereas lipidomics assays in peripheral blood are relatively well-established, the application of spatially- resolved lipidomics in the brain is novel. Bulk lipidomics studies have revealed potential differences in lipid metabolism across aging and disease, but the regional and cell type-specificity of these changes remains unresolved. In particular, given that the brain comprises numerous cell types of multiple lineages with tightly regulated spatial organization and inter-connections, it is likely the lipid profiles, metabolism, and dysregulation are all dramatically non-uniform across the brain. Thus, we propose to provide a map of this non-uniformity in brain tissue would move the field forward substantially in terms of having a universal reference, much as the Allen mouse brain atlas revolutionized researchers' ability to query spatial patterns of gene expression in the brain. We believe that a lipidomics atlas will be transformative in a similar way, especially given the increased focus on lipid dysregulation in neurodegenerative disease. We will test the hypothesis that deficits in the acyl chain remodeling pathway may underlie the changes in metabolic profile such as fatty acid metabolism and functional effects mediated by genes ABCA7, PICALM and BIN1 which have recently been identified associated with Late Onset AD genetic risk. Our continuing studies on phosphoinositide metabolism and the gene network including Synaptojanin1 (Synj1) are highly relevant to PICALM, a phosphoinoistide binding protein, and BIN1, also known as amphiphysin2, which interacts with Synj1 and is likely to mediate phosphoinositide signaling. ABCA7 interestingly, has been shown to transport lysophosphatidylcholine (LPC) a major biochemical intermediate of the Land's cycle and acyl chain remodeling. Recently, ABCA7 haplodefeciency has been shown to disrupt microglia function. It is clear that functional studies to understand phospholipid regional brain distribution, cell specificity and roles in cell-specific functions are critical for gaining understanding of these genes as well as the pathogenesis and disease progression of AD. Ultimately, we will identify biomarkers based on lipids which are dysregulated in brain and show correlated (positive or negative) dysregulation in plasma, which is tractable in the clinic. We hypothesize that re-programming of lipid metabolism is likely to be based on early changes in the Lands Cycle, acyl chain remodeling. This early and stereotypically altered metabolic shift in the lipid profile could ultimately be used for biomarker or therapeutic target discovery in AD. Successful completion of these studies will lead to system-wide, biological insight into the contribution of lipid metabolism to Alzheimer's Disease and validation of a lipid discovery platform which can be applied to future studies for development of biomarkers as well as therapeutic targets.