Format

Send to

Choose Destination
NPJ Aging Mech Dis. 2016;2. pii: 16019. Epub 2016 Sep 22.

Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca2+-Handling Deficits in Alzheimer's Disease Models.

Author information

1
Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, Maryland 21224.
2
Sanders-Brown Center on Aging, and Department of Neurology, University of Kentucky College of Medicine, Lexington, KY 40508.
3
Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205.
4
Department of Molecular and Comparative Pathobiology and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.
5
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.

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.

KEYWORDS:

Alzheimer's disease; amyloid β-peptide; exosomes; extracellular vesicles; glutamate; mitochondria

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center