Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer’s Disease Patients Effect Complement-Mediated Neurotoxicity

Carlos J. Nogueras-Ortiz; Vasiliki Mahairaki; Francheska Delgado-Peraza; Debamitra Das; Konstantinos Avgerinos; Erden Eren; Matthew Hentschel; Edward J. Goetzl; Mark P. Mattson; Dimitrios Kapogiannis

doi:10.3390/cells9071618

Cells (Jul 2020)

Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer’s Disease Patients Effect Complement-Mediated Neurotoxicity

Carlos J. Nogueras-Ortiz,
Vasiliki Mahairaki,
Francheska Delgado-Peraza,
Debamitra Das,
Konstantinos Avgerinos,
Erden Eren,
Matthew Hentschel,
Edward J. Goetzl,
Mark P. Mattson,
Dimitrios Kapogiannis

Affiliations

Carlos J. Nogueras-Ortiz: Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA
Vasiliki Mahairaki: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Francheska Delgado-Peraza: Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA
Debamitra Das: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Konstantinos Avgerinos: Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA
Erden Eren: Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA
Matthew Hentschel: Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA
Edward J. Goetzl: Department of Medicine, University of California, San Francisco, CA 94143, USA
Mark P. Mattson: Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Dimitrios Kapogiannis: Laboratory of Clinical Investigation, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA

DOI: https://doi.org/10.3390/cells9071618
Journal volume & issue: Vol. 9, no. 7
p. 1618

Abstract

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We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD.

Published in Cells

ISSN: 2073-4409 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General): Cytology
Website: https://www.mdpi.com/journal/cells

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