Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model

Abstract

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that affects more than 44 million people worldwide. Despite the high disease burden, there is no effective treatment for people suffering from AD. Mesenchymal stem cells (MSCs) are multipotent stromal cells that have been widely studied due to their therapeutic potential. However, administration of cells has been found to have a multitude of limitations. Recently, extracellular vesicles (EVs) derived from MSCs have been studied as a therapeutic candidate, as they exhibit similar immunoprotective and immunomodulatory abilities as the host human MSCs. Methods: To test the potential therapeutic effects of MSC EVs, human bone-marrow derived MSCs were grown in three-dimensional (3D) cell culture, and small EVs were harvested using differential ultracentrifugation. These small EVs were given to non-transgenic (NT) or 5XFAD (5 familial Alzheimer's disease mutations) mice intranasally (IN) every 4 days for 4 months. The mice were then required to perform a variety of behavioral assays to measure changes in learning and memory. Afterwards, immunohistochemistry was performed on brain slices to measure amyloid beta (Aβ) and glial fibrillary acidic protein (GFAP) levels. Results: The data revealed that 5XFAD mice that received hMSC-EV treatment behaved significantly better in cognitive tests than saline treated 5XFAD mice, with no significant change between EV-treated 5XFAD mice and NT mice. Additionally, we found lower Aβ plaque load in the hippocampus of the EV-treated mice. Finally, less colocalization between GFAP and Aβ plaques was found in the brain of EV-treated mice compared to saline. Conclusions: Taken together, these data suggest that IN administration of MSC-derived EVs can slow down AD pathogenesis.

Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapy for Alzheimer’s Disease: Progress and Opportunity

“…Plenty of studies mainly focus on the status of microglia regulated by MSC-derived EVs. In line with other findings, our study also showed that MSC-derived EVs inhibited astrocytes and microglia activation in the brain of AD mice, indicating that these effects are attributed to immunomodulatory properties of EVs [ 70 , 71 , 81 ]. It should be noted that neuronal networks, astrocytes microglia, oligodendrocytes and the vascular system all contribute to a complex cellular phase of the disease.…”

“…In vivo studies demonstrated improved cognitive function, restored glucose metabolism, and inhibited astrocytes/microglia activation in mice that were administrated with WJ-MSC-derived EVs through an intravenous injection [ 71 ]. Furthermore, an alternative delivery of MSC-derived EVs for therapeutic intervention in AD through the intranasal route has been used in recent studies owing to the safety, low invasive procedure and a higher amount of EVs reaching the brain [ 70 , 80 , 81 ]. Similarly, MSC-derived EVs exhibit neuroprotective and immunomodulatory potential, evidenced by increased dendritic spine density and decreased microglia activation in treated mice [ 80 ].…”

“…Similarly, MSC-derived EVs exhibit neuroprotective and immunomodulatory potential, evidenced by increased dendritic spine density and decreased microglia activation in treated mice [ 80 ]. Another recent study has demonstrated that MSC-derived EVs can lower Aβ plaque burden and decrease the colocalization between Aβ plaque and glial fibrillary acidic protein (GFAP, a reactive astrocyte marker) in the brain [ 81 ]. The therapeutic effects of MSC-derived EVs obtained from the cell and animal models of AD are summarized in Table 1 .…”

“…To our knowledge, robust neurogenesis was observed after MSC-derived EVs treatment primarily via intracerebroventricular injection or intranasal route in comparison with that via systemic route, suggesting that the amount of MSC-derived EVs accumulated in brain reflects the therapeutic efficacy [ 70 , 76 , 80 , 81 , 128 ]. In addition to intranasal delivery, it is feasible to induce permeability by a temporary disruption of the BBB, such as pulsed focused ultrasound (pFUS).…”

Emerging concepts in the treatment of optic neuritis: mesenchymal stem cell-derived extracellular vesicles

“…Intranasally administered EVs have shown promising results in rodent models of Alzheimer Disease, and other models of neurodegeneration [ 123 – 126 ]. Other studies found intranasal administration of EVs reduced neuroinflammation and neurodegeneration in models of MS [ 106 ], Parkinson’s Disease [ 127 ], and prevented cognitive dysfunction in a model of status epilepticus [ 128 ].…”