Journal
NPJ AGING AND MECHANISMS OF DISEASE
Volume 2, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/npjamd.2016.19
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Funding
- Intramural Research Program of the National Institute on Aging (NIA)
- NIA [P30-AG0-28383]
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Alzheimer's disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid beta-peptide (A beta) accumulates in the brain. Extracellular vesicles (EVs), including exosomes, are small 50-150 nm membrane vesicles that have recently been implicated in the prion-like spread of self-aggregating proteins. Here we report that EVs isolated from AD patient cerebrospinal fluid and plasma, from the plasma of two AD mouse models, and from the medium of neural cells expressing familial AD presenilin 1 mutations, destabilize neuronal Ca2+ homeostasis, impair mitochondrial function, and sensitize neurons to excitotoxicity. EVs contain a relatively low amount of A beta but have an increased A beta 42/ A beta 40 ratio; the majority of A beta is located on the surface of the EVs. Impairment of lysosome function results in increased generation of EVs with elevated A beta 42 levels. EVs may mediate transcellular spread of pathogenic A beta species that impair neuronal Ca2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity.
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