Project Grant R01AG085469

BRAIN AND BLOOD N-GLYCOME PROFILING IN ALZHEIMER'S DISEASE - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS A MAJOR FORM OF DEMENTIA, AFFECTING ABOUT 55 MILLIONS OF PEOPLE WORLDWIDE. DESPITE SUBSTANTIAL EFFORTS, WE STILL DO NOT UNDERSTAND ITS UNDERLYING MECHANISMS, AND THUS NO RELIABLE BIOMARKER OR EFFECTIVE TREATMENT HAS YET BEEN DEVELOPED. PROTEIN N-GLYCOSYLATION, THE ENZYMATIC PROCESS OF ADDING N- GLYCANS (I.E., SUGARS) TO PROTEINS, IS THE MOST COMMON POST-TRANSLATIONAL MODIFICATION THAT REGULATES THE FUNCTION OF MOST PROTEINS. ABERRANT N-GLYCOSYLATION HAS BEEN OBSERVED IN KEY AD-RELATED PROTEINS SUCH AS APP, TAU, AND B-SITE APP-CLEAVING ENZYME-1 (BACE1). N-GLYCANS ARE DIVERSE STRUCTURED BIOMOLECULES THAT PLAY CRUCIAL ROLES IN VARIOUS BIOLOGICAL PROCESSES INCLUDING BRAIN DEVELOPMENT AND SIGNAL TRANSDUCTION. ALTERED COMPOSITION AND STRUCTURE OF N-GLYCANS HAVE BEEN ASSOCIATED WITH AD AND NEUROINFLAMMATION. THUS, CHARACTERIZING THE N- GLYCOME (COMPLETE REPERTOIRE OF ALL N-GLYCANS IN A BIOLOGICAL SAMPLE) WILL FACILITATE THE DISCOVERY OF NOVEL BIOMARKERS AND SHED LIGHT ON THE ROLE OF N-GLYCOSYLATION IN AD PATHOLOGY. OUR PRELIMINARY DATA SHOW THAT BASELINE SERUM N-GLYCANS PREDICTS AD ONSET AND COGNITIVE DECLINE OVER TIME, AND ALTERED BRAIN N-GLYCANS ARE ASSOCIATED WITH AD PATHOLOGY. HOWEVER, A COMPREHENSIVE LANDSCAPE OF THE PERIPHERAL AND CENTRAL N-GLYCOME IN RELATION TO AD IS STILL LACKING, ESPECIALLY IN LARGE-SCALE HUMAN POPULATIONS. THE MECHANISMS THROUGH WHICH ABERRANT N-GLYCOME EXPRESSION CONTRIBUTES TO AD ALSO REMAIN AN ENIGMA. WE HYPOTHESIZE THAT DYSREGULATED SERUM N-GLYCOME PRECEDES AND PREDICTS AD ONSET, AND ABERRANT BRAIN N-GLYCOME IS CAUSALLY IMPLICATED IN AD PATHOLOGY. OUR OBJECTIVES ARE TO UNDERSTAND THE MECHANISMS THROUGH WHICH ABERRANT N-GLYCOSYLATION AFFECTS AD AND IDENTIFY CIRCULATING GLYCAN-BASED MARKERS FOR EARLY PREDICTION AND RISK STRATIFICATION. TO ACHIEVE THESE, WE LEVERAGE THE LARGE COLLECTION OF BIOSPECIMENS (ANTEMORTEM SERUM AND PAIRED POSTMORTEM BRAINS) IN TWO COMMUNITY-BASED PROSPECTIVE COHORTS OF AGING AND DEMENTIA (ROS AND MAP). WE WILL USE THE HIGH-RESOLUTION MATRIX-ASSISTED LASER DESORPTION/IONIZATION TIME-OF-FLIGHT MASS SPECTROMETRY (MALDI-TOF-MS) TO COMPREHENSIVELY PROFILE THE BLOOD (SERUM) AND BRAIN N-GLYCOME IN RELATION TO AD (AIMS 1 AND 2). THE POTENTIAL CAUSAL ROLE OF ABERRANT N-GLYCOME EXPRESSION IN AD PATHOLOGY WILL BE EXAMINED BY INTEGRATIVE MULTI-OMICS ANALYSES, FOLLOWED BY FUNCTIONAL VALIDATION IN DROSOPHILA MODELS OF AD (AIM 3). IN SUM, THIS INNOVATIVE PROJECT LEVERAGES THE WEALTH OF DEEP CLINICAL AND NEUROPATHOLOGICAL PHENOTYPES AS WELL AS MULTI-OMICS DATA (E.G., GLYCOMICS, GENOMICS, EPIGENOMICS, AND TRANSCRIPTOMICS) IN THE SAME BRAIN CORTEX, AND PROVIDES UNPRECEDENTED OPPORTUNITIES TO UNCOVER NOVEL MECHANISMS UNDERLYING AD. OUR PROPOSAL BRINGS TOGETHER AN EXCEPTIONALLY STRONG AND UNIQUE MULTI-DISCIPLINARY TEAM WITH COMPLEMENTARY EXPERTISE NEEDED TO ACHIEVE OUR GOALS. FINDINGS OF THIS STUDY WILL SIGNIFICANTLY ENHANCE OUR UNDERSTANDING OF THE MECHANISMS THROUGH WHICH ABERRANT N-GLYCOSYLATION CONTRIBUTES TO AD, AND ARE LIKELY TO LEAD TO NOVEL MECHANISTIC MARKERS FOR EARLY PREDICTION, RISK STRATIFICATION, AND THERAPEUTIC TARGETS TOWARDS PRECISION TREATMENT OF AD.