Implication of Circulating Extracellular Vesicles-Bound Amyloid-42 Oligomers in the Progression of Alzheimer's Disease

Background: The perplex interrelation between circulating extracellular vesicles (cEVs) and amyloid-beta (A beta) deposits in the context of Alzheimer's disease (AD) is poorly understood. Objective: This study aims to 1) analyze the possible cross-linkage of the neurotoxic amyloid-beta oligomers (oA beta) to the human cEVs, 2) identify cEVs corona proteins associated with oA beta binding, and 3) analyze the distribution and expression of targeted cEVs proteins in preclinical participants converted to AD 5 years later (Pre-AD). Methods: cEVs were isolated from 15 Pre-AD participants and 15 healthy controls selected from the Canadian Study of Health and Aging. Biochemical, clinical, lipid, and inflammatory profiles were measured. oA beta and cEVs interaction was determined by nanoparticle tracking analysis and proteinase K digestion. cEVs bound proteins were determined by ELISA. Results: oA beta were trapped by cEVs and were topologically bound to their external surface. We identified surface-exposed proteins functionally able to conjugate oA beta including apolipoprotein J (apoJ), apoE and RAGE, with apoJ being 30- to 130-fold higher than RAGE and apoE, respectively. The expression of cEVs apoJ was significantly lower in Pre-AD up to 5 years before AD onset. Conclusions: Our findings suggest that cEVs might participate in oA beta clearance and that early dysregulation of cEVs could increase the risk of conversion to AD.