Brain glycosphingolipids and Alzheimer's disease

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Alzheimer’s dementia (AD) affects over 35 million people worldwide, and this number is expected to nearly triple by 2050. AD is clinically characterized by progressive cognitive decline; pathologic AD is defined by amyloid plaques and neurofibrillary tangles in the brain. Despite substantial effort, our understanding of its pathophysiology remains incomplete. A thorough understanding of the underlying mechanisms is a prerequisite for discovering novel therapeutic targets. Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone attached to one or more carbohydrates (i.e., glycans). GSLs are especially abundant in the brain and play important roles in brain development, brain aging and neurodegeneration. However, due to technical limitations, our knowledge about the global composition and structures of brain GSLs and their associations with AD pathology remain limited. The mechanisms through which altered GSL expression contributes to AD also remain an enigma. Recently, we have developed several novel technologies for identifying and quantifying intact GSLs (both glycan and diverse lipid forms together as a whole), and for synthesis of GSLs and their derivatives. We have also successfully validated these methods in both human and mouse brain tissue samples. Using these innovative techniques, we will test the hypothesis that altered expression of brain GSLs is causally implicated in AD pathology. Our objectives are to generate the first complete map of brain GSLome (i.e., all GSLs in brain), to identify specific GSLs associated with AD neuropathology (e.g., amyloid-β, neurofibrillary tangles), and to elucidate the mechanisms through which altered expression of GSLs causally contributes to AD pathology. To achieve these goals, we leverage a large collection of human postmortem brain tissue samples (dorsolateral prefrontal cortex, DLPFC) in two community-based cohorts of aging and dementia: Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Deep clinical and neuropathological phenotypes as well as rich omics data (e.g., GWAS, DNA methylation, RNA-seq, proteomics) are already available in both cohorts. In Aim 1, we will generate the first complete map of brain GSLome and identify specific GSLs associated with AD neuropathology. Using a data-driven and system biology approach, Aim 2 will integrate brain GSLome data with other brain omics data, including genomics (GWAS), epigenomics (DNA methylation, histone acetylation, and miRNA), transcriptomics (RNA-seq) and proteomics in the same brain cortex (DLPFC), to decipher the mechanisms through which altered brain GSLs causally contribute to AD pathology. Aim 3 employs a gene-centric approach to functionally validate the top-ranked genes in Drosophila model of AD. Such results will provide novel mechanistic insight into AD pathology and would offer immense opportunities for targeting the GSL pathways in developing novel therapeutics for AD treatment.