FUNCTIONAL ASPECTS OF EXTRACELLULAR VESICLES IN ALZHEIMER'S DISEASE PATHOLOGY: FROM AMYLOID Β AGGREGATION TO NEURONAL NETWORK DYSFUNCTION

Extracellular vesicles (EVs) are emerging as key mediators in sporadic Alzheimer’s disease (sAD), carrying bioactive cargo, including RNA and surface proteins, such as the cellular prion protein (PrP^C), a neuronal Aβ receptor. The aim of this study was to elucidate the molecular, structural, and functional roles of EVs in Aβ aggregation and neuronal dysfunction, and to define the contribution of EV-associated PrP^C and disease-specific EV cargo in sAD.
We combined in vitro neuronal models, structural biology approaches, and analyses of human and mouse brain-derived EVs (BDEVs). PrP^C-expressing/deficient EVs from Neuro-2a cells and brain tissue were incubated with recombinant Aβ and analyzed using small-angle X-ray scattering, super-resolution microscopy, and cryogenic electron tomography. BDEVs from sAD and control frontal cortex autopsies were characterized by nanoparticle tracking analysis, electron microscopy, western blotting, and omics. Human iPSC-derived cortical neurons from healthy donors were treated to assess sAD-EV-mediated functional effects.
PrP^C-expressing EVs showed enhanced Aβ sequestration and fibrillation compared to PrP-deficient EVs, and PrP^C levels positively correlated with Aβ abundance in human sAD-BDEVs. EV markers, particularly those associated with PrP^C-positive EVs, were enriched within Aβ plaques in human tissue and amyloid mouse models. Omic profiling revealed that sAD-derived BDEVs are enriched in metabolic enzymes and synaptic proteins. Functional assays demonstrated that these EV-associated proteins modulate neuronal activity, reducing the network clustering in iPSC-derived cortical neurons.
These findings indicate that EV-associated PrP^C and disease-specific EV cargo contribute to Aβ plaque association and neuronal dysfunction, highlighting EVs as mechanistic drivers and potential biomarkers in sAD.