Mesenchymal stem cell- and extracellular vesicle-based therapies for Alzheimer's disease: progress, advantages, and challenges

Abstract

Alzheimer's disease is a severe, highly disabling neurodegenerative disease, clinically characterized by a progressive decline in cognitive functions, and is the most common form of dementia in the elderly. For decades, the search for disease-modifying therapies has focused on the two main Alzheimer's disease histopathological hallmarks, seeking to prevent, mitigate, or clear the formation of extracellular aggregates of β-amyloid peptide and intracellular neurofibrillary tangles of tau protein, although without clinical success. Mesenchymal stem cell-based therapy has emerged as a promising alternative for the treatment of Alzheimer's disease, especially because it also targets other crucial players in the pathogenesis of the disease, such as neuroinflammation, synaptic dysfunction/loss, oxidative stress, and impaired neurogenesis. Herein, we review current knowledge of the therapeutic potential of mesenchymal stem cells and their extracellular vesicles for Alzheimer's disease, discussing the most recent findings in both preclinical and clinical trials as well as how advanced technologies have helped to overcome some limitations and contributed to stimulate the development of more effective treatments.

Keywords: Alzheimer´s disease; amyloid-β; cell therapy; cell transplantation; exosomes; extracellular vesicles; mesenchymal stem cell; micro vesicles; neuroinflammation; tau protein.

Figure 1

Therapeutic role of mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) in Alzheimer´s disease (AD). MSC neuroprotective benefits are based on their secretome enriched in several soluble molecules such as cytokines and trophic factors, and EVs loaded with proteins, organelles, lipids, and nucleic acids. MSC efficacy can be improved in vitro prior to transplantation, by different preconditioning methods, genetic engineering, and/or nanoparticle labeling to increase homing and the production/release of specific factors. The red arrows indicate the therapeutic role of MSC and MSC-EVs in the AD brain, inhibiting amyloid-β (Aβ) and tau pathology, neuroinflammation, synapse dysfunction, oxidative stress, and neuron loss. ROS: Reactive oxygen species. Created with smart.servier.com.