Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease

Dinkins, Michael B.; Dasgupta, Somsankar; Wang, Guanghu; Zhu, Gu; Bieberich, Erhard

doi:10.1016/j.neurobiolaging.2014.02.012

Cited by 403 publications

(401 citation statements)

References 58 publications

(71 reference statements)

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“…Indeed, they found that systemically administration of GW4869 could reduce the total exosomes in serum and treat allergic, cardiac and Alzheimer's dysfunction 29, 30, 31. Thus, our findings provide a potential method to prevent endothelial inflammation and atherosclerosis.…”

Section: Discussionmentioning

confidence: 63%

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway

Gao

Yuan

et al. 2016

J Cellular Molecular Medi

223

155

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Whether dendritic cell (DC) derived exosomes play a role in the progression of endothelial inflammation and atherosclerosis remains unclear. Using a transwell system and exosome release inhibitor GW4869, we demonstrated that mature DCs contributed to endothelial inflammation and exosomes were involved in the process. To further confirm this finding, we isolated exosomes from bone marrow dendritic cell (BMDC) culture medium (named DC‐exos) and stimulated human umbilical vein endothelial cell (HUVEC) with these DC‐exos. We observed that mature DC‐exos increased HUVEC inflammation through NF‐κB pathway in a manner similar to that of lipopolysaccharide. After a protein array analysis of exosomes, we identified and confirmed tumour necrosis factor (TNF)‐α on exosome membrane being the trigger of NF‐κB pathway in HUVECs. We then performed an in vivo study and found that the aorta endothelial of mice could uptake intravenously injected exosomes and was activated by these exosomes. After a period of 12 weeks of mature DC‐exos injection into ApoE−/− mice, the atherosclerotic lesions significantly increased. Our study demonstrates that mature DCs derived exosomes increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway. This finding extends our knowledge on how DCs affect inflammation and provides a potential method to prevent endothelial inflammation and atherosclerosis.

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Section: Discussionmentioning

confidence: 63%

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway

Gao

Yuan

et al. 2016

J Cellular Molecular Medi

223

155

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“…Exosomes were found to stimulate the aggregation of A␤ by isolating exosomes from brain tissue of the 5ϫFAD mouse model of AD (79). Inhibition of exosome formation in this model using GW4869, an inhibitor of neutral sphingomyelinase, resulted in the reduction of amyloid plaques in the brain.…”

Section: Exosomes and The Transmission Of Ad Pathologymentioning

confidence: 99%

Exosomes in the Pathology of Neurodegenerative Diseases

Howitt

Hill

2016

Journal of Biological Chemistry

230

172

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Edited by Paul FraserMore than 30 years ago, two unexpected findings were discovered that challenged conventional thinking in biology. The first was the identification of a misfolded protein with transmissible properties associated with a group of neurodegenerative diseases known as transmissible spongiform encephalopathies. The second was the discovery of a new pathway used for the extracellular release of biomolecules, including extracellular vesicles called exosomes. Two decades later, the convergence of these pathways was shown when exosomes were found to play a significant role in both the transmission and propagation of protein aggregates in disease. Recent research has now revealed that the majority of proteins involved in neurodegenerative diseases are transported in exosomes, and that external stresses due to age-related impairment of protein quality control mechanisms can promote the transcellular flux of these proteins in exosomes. Significantly, exosomes provide an environment that can induce the conformational conversion of native proteins into aggregates that can be transmitted to otherwise aggregate-free cells in the brain. Here we review the current roles of exosomes in the pathology of neurodegenerative diseases.Exosomes are released into the extracellular environment by the majority of cell types in the body. Originally identified to be involved in the non-degradative removal of the transferrin receptor during the maturation process of reticulocytes (1, 2), exosomes have now also been recognized as an important communication and signaling pathway in the body in both normal and disease settings. Exosomes differ from other extracellular vesicles (EVs) 3 based on the secretion pathway used and the size of the vesicle released. Unlike other EVs that can bud from the plasma membrane, such as microvesicles (3), exosomes are created from intraluminal vesicles that form within multivesicular bodies (MVBs, or multivesicular endosomes). The subsequent fusion of the MVB at the plasma membrane releases these vesicles into the extracellular milieu where they are known as exosomes (Fig. 1). This secretion process results in a large number of exosomes being released in the body, with estimates of 3 ϫ 10 6 exosomes per microliter of blood serum. Recent evidence has highlighted the importance of exosomes both for cellular communication and in the delivery of biomolecules.The function of exosomes differs depending on the cell type from which they originate. Initial in vivo studies identified that exosomes derived from dendritic cells could express MHC class II molecules to promote an immune response (4). Since then, exosomes have been found to function in angiogenesis, inflammation, morphogen transportation, and programmed cell death (5). The richest area of exosome research, however, has come from disease studies, in particular the cancer field. Recent evidence has highlighted a role for exosomes to promote metastasis and regulate tumor immune response (6). Of particular interest is the ability of tumors to rel...

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“…At present there is some controversy in the field as to the role of EVs in AD; while some studies (59)(60)(61) suggest that exosome-associated Aβ is protective, other studies suggest that exosome-associated Aβ contributes neurotoxic amyloid formation (56,(62)(63)(64)(65). Moreover, misfolded tau protein, which is implicated in Aβ aggregate formation, may also be released from neurons via EVs (66).…”

Section: Evs In Physiology and Pathology Of The Nervous Systemmentioning

confidence: 99%

Extracellular vesicles and intercellular communication within the nervous system

Zappulli¹,

Friis²,

Fitzpatrick³

et al. 2016

Journal of Clinical Investigation

199

162

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Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease

Cited by 403 publications

References 58 publications

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway

Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway

Exosomes in the Pathology of Neurodegenerative Diseases

Extracellular vesicles and intercellular communication within the nervous system

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