Whiten, DR;
Brownjohn, PW;
Moore, S;
De, S;
Strano, A;
Zuo, Y;
Haneklaus, M;
... Livesey, FJ; + view all
(2020)
Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer's disease neurons.
Brain Communications
, 2
(2)
, Article fcaa146. 10.1093/braincomms/fcaa146.
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Abstract
In addition to increased aberrant protein aggregation, inflammation has been proposed as a key element in the pathogenesis and progression of Alzheimer’s disease. How inflammation interacts with other disease pathways and how protein aggregation increases during disease are not clear. We used single-molecule imaging approaches and membrane permeabilization assays to determine the effect of chronic exposure to tumour necrosis factor, a master proinflammatory cytokine, on protein aggregation in human-induced pluripotent stem cell-derived neurons harbouring monogenic Alzheimer’s disease mutations. We report that exposure of Alzheimer’s disease neurons, but not control neurons, to tumour necrosis factor induces substantial production of extracellular protein aggregates. Aggregates from Alzheimer’s disease neurons are composed of amyloid-β and α-synuclein and induce significant permeabilization of lipid membranes in an assay of pathogenicity. These findings provide support for a causal relationship between two crucial processes in Alzheimer’s disease pathogenesis and suggest that targeting inflammation, particularly tumour necrosis factor, may have beneficial downstream effects on ameliorating aberrant protein aggregation and accumulation.
| Type: | Article |
|---|---|
| Title: | Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer's disease neurons |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/braincomms/fcaa146 |
| Publisher version: | https://doi.org/10.1093/braincomms/fcaa146 |
| Language: | English |
| Additional information: | Copyright © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | inflammation, protein aggregation, tumour necrosis factor, induced pluripotent stem cells, presenilin-1 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10121876 |
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