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.
Highlights
Accumulation of misfolded proteins produced by neurons, initially extracellular deposits of amyloid-b (Ab), followed by intracellular aggregation of tau are thought to be primary initiating mechanisms in Alzheimer’s disease pathogenesis (Hardy and Higgins, 1992; Hardy and Selkoe, 2002)
Pre-incubation with two tau-directed antibodies that bind to different epitopes had no significant effect, suggesting that tau does not form or contribute to the toxic aggregates produced under these conditions. These results suggest that tumour necrosis factor (TNF) augments the secretion of extracellular Ab and a-synucleincontaining aggregates from presenilin 1 (PSEN1) mutant neurons that have the capacity to permeabilize lipid membranes
We report here that chronic TNF treatment of human PSEN1 mutant neurons, but not healthy control neurons, results in increased release of toxic extracellular protein aggregates
Summary
Accumulation of misfolded proteins produced by neurons, initially extracellular deposits of amyloid-b (Ab), followed by intracellular aggregation of tau are thought to be primary initiating mechanisms in Alzheimer’s disease pathogenesis (Hardy and Higgins, 1992; Hardy and Selkoe, 2002) Downstream of this biochemical phase of Alzheimer’s disease are complex interactions between neurons and astrocytes, microglia and other cell types, resulting in chronic neuroinflammation, synaptic dysfunction and eventually widespread cell loss (De Strooper and Karran, 2016). While inflammation in this context has been thought of as a reactive and secondary process, clinical, genetic and experimental evidence suggests a more central upstream role for immune system involvement in Alzheimer’s disease pathophysiology and progression [reviewed by Heneka et al (2015)], how this initiates is not clear. The mechanisms underlying the relationship between a proinflammatory environment and primary disease phenotypes is yet to be fully elucidated,
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