Acyl chain remodeling and regional lipid dysregulation in alzheimer's disease - accumulating data from human and mouse support the hypothesis that system level lipid disregulation is an early and…

This $342,934.65 project grant from the Department of Health and Human Services National Institutes of Health National Institute on Aging, under the Aging Research program (CFDA 93.866), will fund research into acyl chain remodeling and regional lipid dysregulation in Alzheimer's disease. The Trustees of Columbia University in the City of New York, doing business as Health Sciences Division, will analyze lipid composition in brain regions susceptible to Alzheimer's disease, such as the hippocampus and entorhinal cortex, in mouse models and human brain tissue using imaging mass spectrometry. Researchers will test the hypothesis that docosahexaenoic acid (DHA) accretion is a critical modifier of Alzheimer's-associated behavioral deficits and pathology by generating mouse model strains lacking or overexpressing acyl-CoA synthetase 6, a key mediator of DHA enrichment in the brain. The project aims to integrate data into a publicly available lipid brain atlas and further the understanding of basic metabolic pathways and connectivity in the brain, with the goal of uncovering new biomarkers and therapeutic targets for Alzheimer's disease.

Acyl chain remodeling and regional lipid dysregulation in alzheimer's disease - accumulating data from human and mouse support the hypothesis that system level lipid disregulation is an early and critical factor in etiology and progression of alzheimer's disease (ad). The explosion of 'omics methods in the past decade has resulted in a proliferation of various studies and data sets that interrogate specific regions of the brain. Using imaging mass spectrometry (IMS), our preliminary studies have found regionally differential lipid composition in coronal sections from wild type mouse brain and a mouse model of alzheimer's disease over expressing the amyloid precursor protein (APP) transgene. This regional lipid disregulation requires system-wide interrogation of lipid homeostasis which can singularly be accomplished with lididomics. A candidate based screen of lipid modifying enzymes in mouse embryonic stem cells for resistance to ASS-triggered synapse loss, identified multiple metabolic enzymes which may be responsible for exit of polyunsaturated fatty acids (pufa), specifically docosahexaenoic acid (DHA) from an acyl chain remodeling pathway, the land's cycle. The land's cycle has recently been identified to be dysfunctional in two animal models of ad. In the human context, DHA transport into the brain is aberrant by age 30, in carriers of a variant of apolipoprotein e (APOE4) strongly associated with ad risk. Synthesis of these results with multiple hits from gwas implicating lipid metabolism and transport, strongly support system-wide dyshomeostatis of acyl chain composition in the brain. However, the reports of regionally defined lipid composition are currently limited. We propose to test the hypothesis that acyl chain composition among multiple lipid classes is severely disregulated in brain regions known to be susceptible in ad including hippocampus and entorhynal cortex. Using IMS we will interrogate the lipid composition of mouse models of ad, TG2576 and targeted replacement apoe mice as well as human brain tissue. We will then test the hypothesis that DHA accretion is a critical modifier of ad associated behavioral deficits and pathology in mouse models using knock-out lines of acyl- COA synthetase 6 (ACSL6), a key mediator of DHA enrichment in the brain. We will generate new strains of TG2576 and TRAPOE4 lacking ACSL6 and overexpressing ACSL6 to determine both necessity and sufficiency of DHA brain accretion for ad associated deficits. Finally, we will integrate and assemble our data into a publically available lipid brain atlas. These studies have potential to synthesize accumulating lipidomics data in aging and neurodegenerative disease. The use of spatial lipidomics at scale in the brain has not been yet be comprehensively accomplished, and is required for clear understanding of the basic metabolic pathways thus uncovering connectivity and functionality in the brain. Completion of these studies will represent compelling evidence for the critical nature of lipid composition in basic biology of ad and lead to new strategies for biomarker discovery as well as therapeutic targets.