Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca 2+ -Handling Deficits in Alzheimer's Disease Models
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 s...
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Published in | npj aging and mechanisms of disease Vol. 2 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
2016
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Subjects | |
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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 Ca
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 Ca
handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity. |
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AbstractList | 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 Ca
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 Ca
handling and mitochondrial function, and may thereby render neurons vulnerable to excitotoxicity. |
Author | Mattson, Mark P Kapogiannis, Dimitrios Jicha, Gregory A Witwer, Kenneth W Maharana, Chinmoyee Marosi, Krisztina Eitan, Erez Comotto, James Liu, Dong Hutchison, Emmette R Nigam, Saket M Machairaki, Vasiliki Mustapic, Maja Suire, Caitlin |
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Title | Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca 2+ -Handling Deficits in Alzheimer's Disease Models |
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