Stratification of Brain-Derived Extracellular Vesicles of Alzheimer’s Disease Patients Indicates a Unique Proteomic Content and a Higher Seeding Capacity of Small Extracellular Vesicles

Alzheimer’s disease (AD) is the most prominent form of dementia worldwide. It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner. This has led to the prion-like propagation hypothesis implicating a transfer of pathological tau seeds from cell-to-cell. Human extracellular vesicles isolated from the brain-derived fluid (BD-EVs) of AD patients contain seeds that contribute to this tau pathology spreading. Knowing the rich diversity of EVs, isolation of functional EVs sub-population is required to unravel their implication in the pathophysiology of AD. Here, enriched-small EVs (eSEVs) and enriched-large EVs (eLEVs) were isolated from frozen tissue after collagenase enzymatic brain dissociation to guaranty the best EVs’ integrity. Both AD-derived eSEVs and eLEVs show the presence of GWAS-associated proteins and indicate a specific AD pathophysiological signature. Notably, AD eSEVs contain more proteins relative to the integrin-mediated synaptic signaling, while AD eLEVs proteins were more related to respiratory electron transport and brain-immunity. Injection of these vesicles in transgenic mouse brain revealed that AD-derived eSEVs are more prone than eLEVs to participate to the prion-like propagation and hence represent an interesting therapeutic target.