Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes

Alzheimer's disease (AD) is characterized by the accumulation of beta-amyloid peptide (Ab) in the brain because of an imbalance between A beta production and clearance. Neprilysin (NEP) is the most important A beta-degrading enzyme in the brain. Thus, researchers have explored virus-mediated NEP gene delivery. However, such strategies may entail unexpected risks, and thus exploration of a new possibility for NEP delivery is also required. Here, we show that human adipose tissue-derived mesenchymal stem cells (ADSCs) secrete exosomes carrying enzymatically active NEP. The NEP-specific activity level of 1 mu g protein from ADSC-derived exosomes was equivalent to that of similar to 0.3 ng of recombinant human NEP. Of note, ADSC-derived exosomes were transferred into N2a cells, and were suggested to decrease both secreted and intracellular A beta levels in the N2a cells. Importantly, these characteristics were more pronounced in ADSCs than bone marrow-derived mesenchymal stem cells, suggesting the therapeutic relevance of ADSC-derived exosomes for AD.