Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer's disease neurons. Issue 2 (15th September 2020)

• Record Type: Journal Article
• Authors: Whiten, Daniel R; Brownjohn, Philip W; Moore, Steven; De, Suman; Strano, Alessio; Zuo, Yukun; Haneklaus, Moritz; Klenerman, David; Livesey, Frederick J
• Is Part Of: Brain communications. Volume 2:Issue 2(2020)
• Publication Date: 2020-09-15
• Subjects: inflammation -- protein aggregation -- tumour necrosis factor -- induced pluripotent stem cells -- presenilin-1; 616
• DOI: 10.1093/braincomms/fcaa146
• Languages: English
• ISSNs: 2632-1297

Abstract

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. Abstract : There is a complex interplay between neuroinflammation and protein aggregation in Alzheimer's disease. We show that chronic exposure to the inflammatory cytokine tumour necrosis factor stimulates monogenic Alzheimer's disease neurons to produce significantly more toxic protein aggregates, with no effect on healthy neurons, indicating a causal relationship between neuroinflammation and protein aggregation. Graphical Abstract: