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Pleiotropic roles are proposed for brain extracellular vesicles (EVs) in the development of Alzheimer's disease (AD). Our previous studies have suggested a beneficial role for EVs in AD, where the endosomal system in vulnerable neurons is compromised, contributing to the removal of accumulated material from neurons. However, the involvement of EVs in propagating AD amyloidosis throughout the brain has been considered because the amyloid‐β precursor protein (APP), APP metabolites, and key APP cleaving enzymes were identified in association with EVs. Here, we undertook to determine whether the secretase machinery is actively processing APP in EVs isolated from the brains of wild‐type and APP overexpressing Tg2576 mice. We found that full‐length APP is cleaved in EVs incubated in the absence of cells. The resulting metabolites, both α‐ and β‐APP carboxyl‐terminal fragments and APP intracellular domain accumulate in EVs over time and amyloid‐β dimerizes. Thus, EVs contribute to the removal from neurons and transport of APP‐derived neurotoxic peptides. While this is potentially a venue for propagation of the pathology throughout the brain, it may contribute to efficient removal of neurotoxic peptides from the brain.

Newly identified mitovesicles are a type of extracellular vesicles whose levels and cargo are altered in Down syndrome., Mitochondrial dysfunction is an established hallmark of aging and neurodegenerative disorders such as Down syndrome (DS) and Alzheimer’s disease (AD). Using a high-resolution density gradient separation of extracellular vesicles (EVs) isolated from murine and human DS and diploid control brains, we identify and characterize a previously unknown population of double-membraned EVs containing multiple mitochondrial proteins distinct from previously described EV subtypes, including microvesicles and exosomes. We term these newly identified mitochondria-derived EVs “mitovesicles.” We demonstrate that brain-derived mitovesicles contain a specific subset of mitochondrial constituents and that their levels and cargo are altered during pathophysiological processes where mitochondrial dysfunction occurs, including in DS. The development of a method for the selective isolation of mitovesicles paves the way for the characterization in vivo of biological processes connecting EV biology and mitochondria dynamics and for innovative therapeutic and diagnostic strategies.

Down syndrome (DS) is characterized by cognitive deficits throughout the lifespan and with the development of aging-dependent Alzheimer’s type neuropathology, which is related to the triplication of the amyloid β precursor protein (APP) gene. A dysfunctional endosomal system in neurons is an early characteristic of DS and APP-metabolites accumulate in endosomes in DS neurons. We have previously shown enhanced release of exosomes in the brain of DS patients and the mouse model of DS Ts[Rb(12.17(16))]2Cje (Ts2), and by DS fibroblasts, as compared to diploid controls. Here, we demonstrate that exosome-enriched extracellular vesicles (hereafter called EVs) isolated from the brain of DS patients, Ts2 mice and from the culture media of human DS fibroblasts are enriched in APP carboxyl-terminal fragments (APP-CTFs) as compared with diploid controls. Moreover, APP-CTFs levels increase in an age-dependent manner in EVs isolated from the brain of Ts2 mice. The release of APP-CTFs-enriched exosomes may have a pathogenic role by transporting APP-CTFs into naïve neurons and propagating these neurotoxic metabolites, which are also a source of amyloid β, throughout the brain, but also provides a benefit to DS neurons by shedding APP-CTFs accumulated intracellularly.