Abstract
Alzheimer's disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. Soluble oligomers of the amyloid-β peptide (AβOs) are thought to be proximal neurotoxins involved in early neuronal oxidative stress and synapse damage, ultimately leading to neurodegeneration and memory impairment in AD. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AβOs on hippocampal neurons. To this end, we established transwell cocultures of rat hippocampal neurons and MSCs. We show that MSCs and MSC-derived extracellular vesicles protect neurons against AβO-induced oxidative stress and synapse damage, revealed by loss of pre- and postsynaptic markers. Protection by MSCs entails three complementary mechanisms: 1) internalization and degradation of AβOs; 2) release of extracellular vesicles containing active catalase; and 3) selective secretion of interleukin-6, interleukin-10, and vascular endothelial growth factor to the medium. Results support the notion that MSCs may represent a promising alternative for cell-based therapies in AD.
Highlights
Alzheimer’s disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies
We initially evaluated the effects of exposure of mesenchymal stem cells (MSCs) to AOs (500 nM) by investigating cell viability (Fig. 1, A–C), proliferation (Fig. 1, D–F), oxidative stress (measured by levels of reactive oxygen species (ROS); Fig. 1, G and H), and cellular respiration following exposure to oligomers (Fig. 1I)
Several therapeutic strategies are under investigation to prevent or delay the neurodegenerative process that occurs in AD
Summary
Alzheimer’s disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AOs on hippocampal neurons. To this end, we established transwell cocultures of rat hippocampal neurons and MSCs. We show that MSCs and MSC-derived extracellular vesicles protect neurons against AO-induced oxidative stress and synapse damage, revealed by loss of pre- and postsynaptic markers. Studies employing mesenchymal stem cells (MSCs) from different sources have demonstrated promising results in in vivo AD models (9 –12). We demonstrate that MSCs and MSC-derived EVs block oxidative stress and central nervous system; LAMP-1, lysosome-associated membrane protein 1; PSD-95, postsynaptic density protein 95; ANOVA, analysis of variance
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