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

被引：100

作者：

Eitan E. ^{[1
]}

Hutchison E.R. ^{[1
]}

Marosi K. ^{[1
]}

Comotto J. ^{[1
]}

Mustapic M. ^{[1
]}

Nigam S.M. ^{[1
]}

Suire C. ^{[1
]}

Maharana C. ^{[1
]}

Jicha G.A. ^{[2
]}

Liu D. ^{[1
]}

Machairaki V. ^{[3
]}

Witwer K.W. ^{[4
]}

Kapogiannis D. ^{[1
]}

Mattson M.P. ^{[1
,5
]}

机构：

[1] Laboratory of Neurosciences, National Institute on Aging, NIH, Baltimore, MD

[2] Sanders-Brown Center on Aging, and Department of Neurology, University of Kentucky College of Medicine, Lexington, KY

[3] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD

[4] Department of Molecular and Comparative Pathobiology and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD

[5] Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD

来源：

npj Aging and Mechanisms of Disease | / 2卷 / 1期

关键词：

D O I：

10.1038/npjamd.2016.19

中图分类号：

学科分类号：

摘要：

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. © The Author(s) 2016.

引用

共 76 条

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