Alzheimer’s disease (AD) is considered by many to be a synaptic failure. Synaptic function is in fact deeply affected in the very early disease phases and recognized as the main cause of AD-related cognitive impairment. While the reciprocal involvement of amyloid beta (Aβ) and tau peptides in these processes is under intense investigation, the crucial role of extracellular vesicles (EVs) released by different brain cells as vehicles for these molecules and as mediators of early synaptic alterations is gaining more and more ground in the field. In this review, we will summarize the current literature on the contribution of EVs derived from distinct brain cells to neuronal alterations and build a working model for EV-mediated propagation of synaptic dysfunction in early AD. A deeper understanding of EV–neuron interaction will provide useful targets for the development of novel therapeutic approaches aimed at hampering AD progression.

Human mesenchymal stem cells modulate the immune response and are good candidates for cell therapy in neuroinflammatory brain disorders affecting both adult and premature infants. Recent evidence indicates that through their secretome, mesenchymal stem cells direct microglia, brain-resident immune cells, toward pro-regenerative functions, but the mechanisms underlying microglial phenotypic transition are still under investigation. Using an in vitro coculture approach combined with transcriptomic analysis, we identified the extracellular matrix as the most relevant pathway altered by the human mesenchymal stem cell secretome in the response of microglia to inflammatory cytokines. We confirmed extracellular matrix remodeling in microglia exposed to the mesenchymal stem cell secretome via immunofluorescence analysis of the matrix component fibronectin and the extracellular crosslinking enzyme transglutaminase-2. Furthermore, an analysis of hallmark microglial functions revealed that changes in the extracellular matrix enhance ruffle formation by microglia and cell motility. These findings point to extracellular matrix changes, associated plasma membrane remodeling, and enhanced microglial migration as novel mechanisms by which mesenchymal stem cells contribute to the pro-regenerative microglial transition.