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

TLDR

Alzheimer’s disease is marked by β‑amyloid accumulation due to impaired clearance, with neprilysin being the principal brain enzyme that degrades Aβ. The study investigates a safer alternative to viral NEP gene delivery by determining whether adipose‑derived mesenchymal stem cells can supply active neprilysin through exosomes. Human adipose‑derived MSCs secrete exosomes containing enzymatically active neprilysin that lower β‑amyloid levels in neuronal cells, outperforming bone‑marrow MSC exosomes and suggesting therapeutic relevance for AD.

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ) in the brain because of an imbalance between Aβ production and clearance. Neprilysin (NEP) is the most important Aβ-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 μg protein from ADSC-derived exosomes was equivalent to that of ~ 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 Aβ 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.