Extracellular vesicle-associated aβ mediates trans-neuronal bioenergetic and ca2+-handling deficits in alzheimer’s disease models

Erez Eitan, Emmette R. Hutchison, Krisztina Marosi, James Comotto, Maja Mustapic, Saket M. Nigam, Caitlin Suire, Chinmoyee Maharana, Gregory A. Jicha, Dong Liu, Vasiliki Machairaki, Kenneth Whitaker Witwer, Dimitrios Kapogiannis, Mark P. Mattson

Research output: Contribution to journalArticle

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), 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 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 of EVs with elevated Aβ42 levels. EVs may mediate transcellular spread of pathogenic Aβ species that impair neuronal Ca2+ handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity.

Original languageEnglish (US)
Article number16019
Journalnpj Aging and Mechanisms of Disease
Volume2
Issue number1
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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    Eitan, E., Hutchison, E. R., Marosi, K., Comotto, J., Mustapic, M., Nigam, S. M., Suire, C., Maharana, C., Jicha, G. A., Liu, D., Machairaki, V., Witwer, K. W., Kapogiannis, D., & Mattson, M. P. (2016). Extracellular vesicle-associated aβ mediates trans-neuronal bioenergetic and ca2+-handling deficits in alzheimer’s disease models. npj Aging and Mechanisms of Disease, 2(1), [16019]. https://doi.org/10.1038/npjamd.2016.19