Figure 8.

Model for synaptic dysfunction propagation mediated by large Aβ-EVs in Alzheimer’s disease. We propose the following model to explain Aβ-EV implication in the onset and propagation of synaptic dysfunction. In the early stages of Alzheimer’s disease, Aβ starts to accumulate in specific areas of the brain, where it is internalized by microglia (1) and re-secreted in toxic form in association with EVs (2): the higher the Aβ cell load, the higher the Aβ content (as indicated by Bafilomycin experiments showed in this paper). Aβ-EVs induce synaptic alterations at the site of adhesion (3) and, by moving along axonal projection (4), can reach connected neurons (5). While small EVs are internalized by neurons and travel inside neuronal axons to trans-synaptically transfer their cargo (so far reported for small EVs released by primary neurons or isolated from Alzheimer patients’ brains),^80–82 large EVs, likely too big to be transported intracellularly, move at the axonal surface towards synaptically connected cells.