Optimizing Small and Large Brain-Derived Extracellular Vesicle Purification Reveals Critical Pathways in Alzheimer's Disease Patients

ABSTRACT: At this day, Alzheimer’s disease 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. Extracellular vesicles have been described as one of the mechanisms contributing to this intercellular transfer of tau seeds. Thus far, we and others demonstrated that human EVs from the brain-derived fluid (BD-EVs) of AD patients contain the capacity to induce tau seeding in vitro and in vivo. Based on these findings and the rich diversity of BD-EVs, we studied BD-EVs sub-populations in AD patients. Here, enriched-small and enriched-large EVs were isolated from two distinct enzymatic brain dissociation protocols. Proteomic analysis then aimed to define the optimal brain dissociation enzyme resulting in well-preserved EVs. We demonstrated that collagenase enzymatic brain dissociation not only results in a high EVs protein yield but also allowed us to detect more transmembrane proteins for both enriched-large and enriched-small EVs in comparison to papain dissociation. Proteomic content analysis of collagenase-derived AD-EVs revealed the increased presence of integrin-mediated synaptic signalling, brain-immunity and GWAS-associated proteins. Although, enriched-large EVs contain more GWAS-associated proteins then enriched-small EVs. This enriched small and large EV sub-population characterization drives comprehension of AD associated pathophysiologic mechanisms potentially mediated through EVs.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Extracellular Vesicle

DISEASE(S): Alzheimer's Disease

SUBMITTER: Soulaimane Aboulouard  

LAB HEAD: Michel Salzet

PROVIDER: PXD055734 | Pride | 2025-12-15

REPOSITORIES: Pride