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

阿尔茨海默病人和小鼠大脑中脂质组的空间失调

基本信息

批准号：
10705302
负责人：
Laura Beth Johnson McIntire
金额：
$ 67.45万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705302
关键词：
Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Animal Model Animals Apolipoprotein E Atlases Autopsy Behavioral Binding Proteins Biochemical Biological Biological Assay Biological Markers Brain Brain Diseases Brain region Cells Cerebrospinal Fluid Characteristics Clinic Cognitive deficits Data Disease Disease Progression Docosahexaenoic Acids Enzymes Freezing Future Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Risk Genetic study Head Hippocampus Homeostasis Human Human Genetics Image In Situ Inositol Late Onset Alzheimer Disease Lecithin Lipids Lysophosphatidylcholines Manuscripts Maps Mediating Memory Metabolic Metabolic Pathway Metabolism Methods Microglia Mus Neurodegenerative Disorders Nonesterified Fatty Acids PLCgamma2 Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phase Phenocopy Phosphatidylethanolamine Phosphatidylinositols Phospholipase A2 Phospholipid Metabolism Phospholipids Phosphoric Monoester Hydrolases Plasma Polyphosphates Polyunsaturated Fatty Acids Prefrontal Cortex Preparation Radiolabeled Reporting Research Personnel Resolution Role SYNJ1 gene Signal Transduction Specificity Stereotyping System Testing Tissues Validation Variant Work abeta accumulation age related amphiphysin apolipoprotein E-4 biomarker development biomarker identification brain tissue cell type cholesterol transporters comparison control entorhinal cortex exhaustion familial Alzheimer disease fatty acid metabolism frontal lobe gene network genetic risk factor genetic variant genome wide association study human disease immunocytochemistry innovation insight lipid metabolism lipidome lipidomics lysophosphatidylinositol mass spectrometric imaging metabolic profile mild cognitive impairment mouse model multidimensional data novel participant enrollment peripheral blood phospholipase D2 public database religious order study tau Proteins therapeutic target tissue processing transcriptomics

项目摘要

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.

尽管脂质组学在外周血中的应用相对完善，但空间-