ABSTRACT
The critical role of neuroinflammation in favoring and accelerating the pathogenic process in Alzheimer's disease (AD) increased the need to target the cerebral innate immune cells as a potential therapeutic strategy to slow down the disease progression. In this scenario, mesenchymal stem cells (MSCs) have risen considerable interest thanks to their immunomodulatory properties, which have been largely ascribed to the release of extracellular vesicles (EVs), namely exosomes and microvesicles. Indeed, the beneficial effects of MSC-EVs in regulating the inflammatory response have been reported in different AD mouse models, upon chronic intravenous or intracerebroventricular administration. In this study, we use the triple-transgenic 3xTg mice showing for the first time that the intranasal route of administration of EVs, derived from cytokine-preconditioned MSCs, was able to induce immunomodulatory and neuroprotective effects in AD. MSC-EVs reached the brain, where they dampened the activation of microglia cells and increased dendritic spine density. MSC-EVs polarized in vitro murine primary microglia toward an anti-inflammatory phenotype suggesting that the neuroprotective effects observed in transgenic mice could result from a positive modulation of the inflammatory status. The possibility to administer MSC-EVs through a noninvasive route and the demonstration of their anti-inflammatory efficacy might accelerate the chance of a translational exploitation of MSC-EVs in AD.
Subject(s)
Alzheimer Disease/therapy , Extracellular Vesicles/transplantation , Immunomodulation , Mesenchymal Stem Cells/metabolism , Neuroprotection , Administration, Intranasal , Alzheimer Disease/pathology , Animals , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Biomarkers/metabolism , Calcium-Binding Proteins/metabolism , Cell Polarity , Cells, Cultured , Cytokines/metabolism , Dendritic Spines/metabolism , Disease Models, Animal , Humans , Inflammation/pathology , Mice, Inbred C57BL , Mice, Transgenic , Microfilament Proteins/metabolism , Microglia/pathology , PhenotypeABSTRACT
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 ß-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 Aß 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 ß-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.
Subject(s)
Extracellular Vesicles/transplantation , Mesenchymal Stem Cells/metabolism , Plaque, Amyloid/therapy , Alzheimer Disease/genetics , Alzheimer Disease/therapy , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Cerebral Cortex/metabolism , Disease Models, Animal , Extracellular Vesicles/metabolism , Female , Hippocampus/metabolism , Male , Mesenchymal Stem Cell Transplantation/methods , Mice , Mice, Inbred C57BL , Neurites/metabolismABSTRACT
No cure yet exists for devastating Alzheimer's disease (AD), despite many years and humongous efforts to find efficacious pharmacological treatments. So far, neither designing drugs to disaggregate amyloid plaques nor tackling solely inflammation turned out to be decisive. Mesenchymal stem cells (MSCs) and, in particular, extracellular vesicles (EVs) originating from them could be proposed as an alternative, strategic approach to attack the pathology. Indeed, MSC-EVs-owing to their ability to deliver lipids/proteins/enzymes/microRNAs endowed with anti-inflammatory, amyloid-ß degrading, and neurotrophic activities-may be exploited as therapeutic tools to restore synaptic function, prevent neuronal death, and slow down memory impairment in AD. Herein the results presented in the most recently published studies on this topic are critically evaluated, providing a strong rationale for possible employment of MSC-EVs in AD. Also see the video abstract here https://youtu.be/tBtDbnlRUhg.
