Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer’s disease neurons

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 permeabilisation assays to determine the effect of chronic exposure to TNF, 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, but not control, neurons to TNF induces substantial production of extracellular protein aggregates. Aggregates from Alzheimer’s disease neurons are composed of amyloid-β and α-synuclein and induce significant permeabilisation 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 TNF, may have beneficial downstream effects on ameliorating aberrant protein aggregation and accumulation.

Defective lysosomal acidification contributes to TNFR1 mediated neuronal necroptosis in Alzheimer’s disease

“…Aβ accumulation has been shown to lead to necroptosis in AD via microglia activation and cytokine production [25]. Furthermore, Aβ can act as DAMPs to increase the expression of proinflammatory cytokines [54] and elevated cytokine production can further lead to increased toxic protein expression and aggregation which results in an autocatalytic process that propagates the inflammatory processes [55]. Hence, targeting TNFR1 induced necroptosis by promoting autolysosomal degradation represents an important strategy in ameliorating the accumulation of toxic necrosome molecules and protein aggregates [55].…”

The Role of the Circadian System in Attention Deficit Hyperactivity Disorder

“…Interestingly, TNF-α is rhythmically expressed in the hypothalamus in vivo (Floyd and Krueger 1997) and in primary microglia in vitro, and its expression in response to immune challenge in primary microglia is attenuated after treatment with a Rev-Erbα agonist (Wolff et al 2020), suggesting that it may mediate coordination between microglial and astrocyte timekeepers. A recent study in human iPSC-derived neurons from patients with familial AD showed that TNF-α application accelerates the production of protein aggregates, including amyloid β (Whiten et al 2020), supporting a role for this cytokine in AD pathogenesis and emphasising the importance of understanding the interactions between the circadian clock and cytokines such as TNF-α, and their effect on glial function.…”

Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome

“…In AD, elevated levels of tumor necrosis factor-α (TNF-α) may play a significant role in exacerbating amyloidosis [ 90 , 91 ], and IGF-1 attenuate amyloidosis by antagonizing TNF-α [ 83 ]. Recent researches have showed that altered CP function can exacerbate Aβ accumulation in the brain [ 73 , 92 ], and numerous in-vitro studies have shown that IGF-1 can maintain tight junction stability in CP epithelial cells [ 92 , 93 ].…”