Abstract
Proteins implicated in neurodegenerative conditions such as Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) have been identified in bodily fluids encased in extracellular vesicles called exosomes. Whether exosomes found in DLB patients can transmit pathology is not clear. In this study, exosomes were successfully harvested through ultracentrifugation from brain tissue from DLB and AD patients as well as non-diseased brain tissue. Exosomes extracted from brains diagnosed with either AD or DLB contained aggregate-prone proteins. Furthermore, injection of brain-derived exosomes from DLB patients into the brains of wild type mice induced α-synuclein (α-syn) aggregation. As assessed through immunofluorescent double labeling, α-syn aggregation was observed in MAP2+, Rab5+ neurons. Using a neuronal cell line, we also identified intracellular α-syn aggregation mediated by exosomes is dependent on recipient cell endocytosis. Together, these data suggest that exosomes from DLB patients are sufficient for seeding and propagating α-syn aggregation in vivo.
Highlights
Misfolded protein aggregates are a pathological hallmark of age-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) [7, 26]
Utilizing biochemical techniques and animal models, we show that brain exosome cargo isolated from AD and DLB brain tissue contain Aβ and tau, with exosomes derived from DLB brain tissue containing α-syn
Patient brains were collected by the UCSD Alzheimer Disease Research Center (ADRC) Neuropathology Core and sagittally divided at autopsy; the left hemibrain was fixed in 10% buffered formalin for neuropathological analysis and the right frozen at −70 °C for subsequent exosome isolation
Summary
Misfolded protein aggregates are a pathological hallmark of age-related neurodegenerative disorders such as Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) [7, 26]. Termed proteinopathies, both disorders result in synaptic dysfunction, neuron loss and cognitive decline [2, 26]. Patients with the “plaque-only” variant of AD contain Lewy Bodies within the neocortex and brainstem [13, 21]. Such heterogeneity between AD and DLB obfuscates proper treatment and diagnosis
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