The Role of Extracellular Vesicles in Alzheimer’s disease: from pathophysiology to Aβ aggregation

The discovery of new strategies and targets that foster natural response mechanisms in sporadic Alzheimer’s disease (sAD) might open the door to new non-invasive therapies. In this project, we hypothesized that the extracellular vesicles (EVs) secreted by the neural cells are carriers of mRNA, miRNA, enzymes, and surface proteins (such as the cellular prion protein (PrPC)) that may activate survival and protective mechanisms in sAD such as the aggregation of amyloid toxic species (Aβ). Here, we have deeply characterized EVs derived from the brain tissue (BDEV) of sAD patients and studied the molecular mechanism regulating their function during the progression of the pathology using a novel non-enzymatic disaggregation method. Our results demonstrate that the sAD-BDEVs express the classical AD histopathological hallmarks, Aβ and p-Tau, and more than 150 differentially expressed proteins that may explain their role in AD pathophysiology.

Moreover, we observed a positive correlation between BDEVs associated Aβ amounts and BDEVs-PrPC. Likewise, EV markers and PrPC expression were correlated in the Aβ plaques biochemically isolated from sAD human postmortem and mice brain tissues. Furthermore, in order to validate the functional role of the sAD-EVs in the neurons, human induced pluripotent stem cell (hiPSC)-derived cortical neuronal cultures were treated with sAD patient-derived EVs. The role of PrP on EVs in modulating Aβ toxicity was evaluated by treating N2a with PrP-KO and PrP-Wt EVs from N2a cells together with Aβ recombinant protein. Our preliminary results are promising for understanding the relevance of PrP-EV in the regulation of AD toxicity. Our data suggests a clear role of EV-expressed PrPC in the association of EVs to the amyloid plaques in AD. Taken together with the mouse model and in vitro data, we conclude that PrPC expression on EVs is crucial for their Aβ sequestration,potentially leading to plaque formation in AD