title: Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca2+-Handling Deficits in Alzheimer's Disease Models.
abstract: Alzheimer's Disease (AD) is an age-related neurodegenerative disorder in which aggregation-prone neurotoxic amyloid β-peptide (Aβ) accumulates in the brain. Extracellular vesicles (EVs) are small 50-150 nanometer 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 CSF 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 Aβ but have an increased Aβ42/ Aβ40 ratio; the majority of Aβ is located on the surface of the EVs. Impairment of lysosome function results in increased generation EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species and that impair neuronal Ca2+handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Erez
authors.initials: E
authors.lastname: Eitan
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Emmette R
authors.initials: ER
authors.lastname: Hutchison
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Marosi
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: James
authors.initials: J
authors.lastname: Comotto
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Maja
authors.initials: M
authors.lastname: Mustapic
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Saket M
authors.initials: SM
authors.lastname: Nigam
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Suire
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Chinmoyee
authors.initials: C
authors.lastname: Maharana
authors.affiliation: Sanders-Brown Center on Aging, and Department of Neurology, University of Kentucky College of Medicine, Lexington, KY 40508.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Jicha
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Machairaki
authors.affiliation: Department of Molecular and Comparative Pathobiology and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Witwer
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kapogiannis
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
keywords: Alzheimer's disease; amyloid β-peptide; exosomes; extracellular vesicles; glutamate; mitochondria