Project Grant RF1AG075992

NCRNAS IN PLASMA EVS OF AD PATIENTS AND THEIR DISCRIMINATORY POWER AS BIOMARKERS - ALZHEIMER'S DISEASE IS THE MOST COMMON AND ECONOMICALLY IMPACTFUL FORM OF DEMENTIA. APPROACHES BASED ON CEREBROSPINAL FLUID AND BLOOD HAVE BEEN ESTABLISHED TO MEASURE THE LEVELS OF AMYLOID BETA AND HYPERPHOSPHORYLATED TAU TO FACILITATE EARLY DIAGNOSIS OF AD OR TO MONITOR THE EFFECTS OF THERAPEUTICS AND PROGRESSION OF THE DISEASE. PLASMA EXTRACELLULAR VESICLES (EVS) AND THEIR CARGO PRESENT AN OPPORTUNITY TO ISOLATE AND PROFILE MOLECULES ASSOCIATED WITH HUMAN PATHOLOGICAL CONDITIONS. WE HAVE RECENTLY DISCOVERED SMALL NUCLEOLAR NON-CODING RNAS (SNORNAS) HIGHLY ENRICHED IN PLASMA EVS OF AD PATIENTS COMPARED TO NON-DEMENTED CONTROLS. WE POSIT THAT TAU AGGREGATES IRREVERSIBLY BIND SNORNAS PREVENTING THEM FROM PERFORMING THEIR NORMAL FUNCTION RESULTING IN A COMPENSATORY INCREASE OF THEIR EXPRESSION IN AD BRAINS. OUR HYPOTHESIS IS THAT THE EXPRESSION OF CERTAIN SNORDS AND THEIR SECRETION IN NEURON DERIVED EVS IS INCREASED WITH THE PROGRESSION OF AD. SMALL NON-CODING NUCLEOLAR SNORNAS MIGHT REPRESENT IDEAL BIOMARKERS, COMPARED WITH PROTEINS AND/OR MRNAS, BECAUSE OF THE PROTECTIVE EFFECT OF PLASMA EV AND THE UNPRECEDENTED SENSITIVITY OF DETECTION BY DDPCR TECHNOLOGY - DOWN TO SINGLE TRANSCRIPTS. THIS PROPOSAL'S PRIMARY GOALS ARE: 1) TO TEST AND VALIDATE THE DIAGNOSTIC ACCURACY OF SNORD115 AND SNORD116 DDPCR ASSAYS IN HUMAN PLASMA; 2) TO UNDERSTAND THE NATURE OF THE ASSOCIATIONS BETWEEN THE ABUNDANCE OF PARTICULAR SNORDS IN AD PLASMA EVS, THEIR EXPRESSION LEVEL IN BRAIN, THE DISEASE STATE AND PROGRESSION, AND IF THERE IS AN ASSOCIATION WITH APOE GENOTYPE; 3) TO TEST FOR EPIGENETIC MECHANISMS UNDERLYING THE CHANGES IN ABUNDANCE OF SNORDS, AND 4) USING AD MOUSE MODELS TO REVEAL THE EFFECT OF AMYLOID AND TAU AGGREGATION ON ISF, CSF AND PLASMA EVS CARGO. A BETTER UNDERSTANDING OF THE UNDERLYING REGULATORY GENOMIC, EPIGENOMIC, AND CELLULAR MECHANISMS RESPONSIBLE FOR THE DIFFERENCES IN THE ENRICHMENT OF SNORDS IN PLASMA EVS OF AD PATIENTS COMPARED TO CONTROLS WOULD HELP UNDERSTAND ESSENTIAL ASPECTS OF APOE MEDIATED RISK OF AD AND IN ESTABLISHING RELIABLE DIAGNOSTIC STRATEGIES.