Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-β oligomers

• Published in: The Journal of biological chemistry Vol. 293; no. 6; pp. 1957 - 1975
• Main Authors: de Godoy, Mariana A., Saraiva, Leonardo M., de Carvalho, Luiza R.P., Vasconcelos-dos-Santos, Andreia, Beiral, Hellen J.V., Ramos, Alane Bernardo, Silva, Livian R. de Paula, Leal, Renata B., Monteiro, Victor H.S., Braga, Carolina V., de Araujo-Silva, Carlla A., Sinis, Leandro C., Bodart-Santos, Victor, Kasai-Brunswick, Tais Hanae, Alcantara, Carolina de Lima, Lima, Ana Paula C.A., da Cunha-e Silva, Narcisa L., Galina, Antonio, Vieyra, Adalberto, De Felice, Fernanda G., Mendez-Otero, Rosalia, Ferreira, Sergio T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.02.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer’s disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; amyloid-β; Animals; catalase; Cell Biology; Cells, Cultured; Coculture Techniques; cytokine action; endocytosis; extracellular vesicles; Extracellular Vesicles - genetics; Extracellular Vesicles - metabolism; hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Humans; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Male; mesenchymal stem cells (MSCs); Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Neurons - cytology; Neurons - metabolism; oligomers; Oxidative Stress; Rats; Rats, Wistar; synapse; Synapses - metabolism; Vascular Endothelial Growth Factor A - metabolism; extracellular vesicles; Alzheimer’s disease; hippocampus; mesenchymal stem cells (MSCs); oligomers; amyloid-β; endocytosis; synapse; catalase; oxidative stress; cytokine action; Alzheimer's disease
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M117.807180

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.