Extracellular Vesicles as a Neprilysin Delivery System Memory Improvement in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative brain disorder which has no effective treatment yet due to the blood barrier in the brain that limits the drugs with the potential of disease improvement. Extracellular vesicles (EVs) are biocompatible nanoparticles with a lipid membrane. These vesicles are secreted from various cells such as mesenchymal stem cells (MSCs) and can pass through biological barriers for transfer of information such as signals or be used as carriers for various proteins like Neprilysin (NEP). NEP is an active enzyme in the clearance of abnormal aggregated beta-amyloid sheets in the brain. In the present study, we used EVs to carry NEP for memory improvement in Alzheimer’s disease. For this purpose, bone marrow MSCs were isolated from rat femur. Stemness evaluation of established cells was characterized by differentiation potency and specific markers with flowcytometry. EVs were isolated from MSCs supernatant by ultracentrifugation and analyzed by scanning electron microscopy (SEM), dynamic light scattering (DLS) and western blotting. EVs were loaded with NEP by freeze-thaw cycle and then administrated intranasally in a rat model of the AD for 14 days. Our findings showed EV-loaded NEP caused a decrease in IL-1beta and also BAX but an increase in BCL2 expression level in the rat brain. Altogether, these data showed that EV-loaded NEP can improve brain-related behavioural function which may be mediated through the regulation of inflammation and apoptosis. These findings suggest that EV-loaded NEP can be considered as a potential drug delivery system for the improvement of AD.