Intracerebral Injection of Extracellular Vesicles from Mesenchymal Stem Cells Exerts Reduced Aβ Plaque Burden in Early Stages of a Preclinical Model of Alzheimer’s Disease

Abstract

Bone marrow Mesenchymal Stem Cells (BM-MSCs), due to their strong protective and anti-inflammatory abilities, have been widely investigated in the context of several diseases for their possible therapeutic role, based on the release of a highly proactive secretome composed of soluble factors and Extracellular Vesicles (EVs). BM-MSC-EVs, in particular, convey many of the beneficial features of parental cells, including direct and indirect β-amyloid degrading-activities, immunoregulatory and neurotrophic abilities. Therefore, EVs represent an extremely attractive tool for therapeutic purposes in neurodegenerative diseases, including Alzheimer’s disease (AD). We examined the therapeutic potential of BM-MSC-EVs injected intracerebrally into the neocortex of APPswe/PS1dE9 AD mice at 3 and 5 months of age, a time window in which the cognitive behavioral phenotype is not yet detectable or has just started to appear. We demonstrate that BM-MSC-EVs are effective at reducing the Aβ plaque burden and the amount of dystrophic neurites in both the cortex and hippocampus. The presence of Neprilysin on BM-MSC-EVs, opens the possibility of a direct β-amyloid degrading action. Our results indicate a potential role for BM-MSC-EVs already in the early stages of AD, suggesting the possibility of intervening before overt clinical manifestations.

Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease

“…Recent studies, including ours showing a potential role for MSC‐EVs already in the early stages of AD, 34 sustain the use of MSC‐EVs to exert beneficial effects in animal models of AD through the regulation of the inflammatory and oxidative processes 32,33 . However, in these studies, EV administration was performed intravenously or intracerebroventricularly for weeks or months in APP/PS1 AD mice.…”

“…EV quantification was performed by determination of the protein contents by bicinchoninic acid assay (BCA; Thermo Fisher Scientific). For size distribution and concentration, EVs were diluted in 1 mL of sterile PBS and subjected to nanoparticle tracking analysis (NTA) by NS300 instrument (Malvern, Worcestershire, UK; see also Reference 34).…”

“…Noteworthy, such approaches also boost the release of highly immunomodulant EVs that successfully target inflammatory and oxidative processes in different pathological contexts, including AD 31‐33 . So far, the in vivo studies investigating MSC‐EV beneficial effects in AD models have exploited chronic treatments (weeks/months), primarily administering EVs via systemic route 32 or by intracerebroventricular (ICV) injection 33,34 showing either partial rescue of the pathology 32,33 or a preventive action in reducing the Aβ plaque burden and the amount of dystrophic neurites 34 . In our study, we tested, for the first time, the efficacy of the intranasal injection of cytokine‐preconditioned MSC‐EVs in 3xTg AD mice.…”

Human Pluripotent Stem Cell-Derived Extracellular Vesicles: Characteristics and Applications

“…91 MSC-EVs carry active neprelysin, an enzyme that can degrade Ab; therefore, MSC-EVs have been shown to reduce the Ab plaque burden and the amount of dystrophic neurites in both the cortex and hippocampus in AD mice. 92 The communication of astrocytes and neurons is mediated by MSC-EVs containing miR-133. 35 miR-133 was downregulated after rat brain ischemia, which can be relieved by EVs containing miR-133.…”

Influence of species and processing parameters on recovery and content of brain tissue-derived extracellular vesicles

“…They can carry disease-associated agents such as amyloid-beta (Aβ) [4][5][6][7] and tau [6][7][8] proteins, which may promote neurodegenerative and inflammatory diseases. However, EVs may also exert protective functions in the CNS by distributing anti-inflammatory factors [9][10][11] . While brain-derived EVs (bdEVs) may leave the brain and betray the state of the CNS as biomarkers in blood and other peripheral fluids, bdEVs are first found in the tissue interstitial space 12 and may be most likely to act locally.…”