Large extracellular vesicles containing mitochondria (EVMs) derived from Alzheimer’s disease cells harbor pathologic functional and molecular profiles and spread mitochondrial dysfunctions

In addition to small extracellular vesicles known as exosomes, cells release large extracellular vesicles containing mitochondria (EVMs). The molecular and functional characteristics of EVMs, as well as the impact of EVMs on the spreading of mitochondrial dysfunction between cells, remain unknown in the context of Alzheimer’s Disease (AD). Here, we provide an ultrastructural, biochemical, and functional characterization of EVMs isolated from neuroblastoma cells expressing the amyloid precursor protein with the familial Swedish mutations (APPswe). We identify differential proteomic and lipidomic signatures in APPswe-derived EVMs compared to control EVMs and revealed a specific proteomic profile in EVMs derived from fibroblasts of AD patients at the prodromal stage of the disease. Our findings show that the pathogenic accumulation of APP-C terminal fragments (APP-CTFs) potentiates the secretion of EVMs through plasma membrane budding. We demonstrate that APP-CTFs loaded EVMs are active carriers of dysfunctional mitochondria mediating the transfer of mitochondrial pathology between cells.