TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer’s disease hippocampus

Abstract

The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer’s disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3+ and phosphoMLKL+ neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.

Gut microbiota from patients with mild COVID-19 cause alterations in mice that resemble post-COVID syndrome

“…Conversely, we found enrichment of Necroptosis-related pathways in the post-COVID humanized microbiota vehicle mice that were reduced in post-COVID humanized microbiota probiotic-treated mice. This result might be associated with the effect of the probiotic counteracting the increase in TNF-α expression since this cytokine triggers this kind of neuronal cell death [100,101]. Accordingly, with these data, we also observed a neuroprotective effect of B. longum that prevented memory impairment induced in a murine model of coronavirus lung infection.…”

Supramolecular organizing centers at the interface of inflammation and neurodegeneration

“…This suggests that necrosome can be activated within neurons, directly causing neuronal death ( 308 ). Building on these findings, another study demonstrated co-localization of these proteins within the same neurons upon their exposure to TNFα and co-immunoprecipitation of pRIP3 and MLKL, which additionally strengthens the argument of these proteins interacting to form necrosome within neurons ( 309 ).…”

“…Necroptosis is closely associated with the pathogenesis of various neurodegenerative diseases ( 279 , 306 ), such as AD ( 307 – 309 ), PD ( 310 , 311 ), ALS ( 312 , 313 ), and multiple sclerosis ( 314 , 315 ). Recently, a direct link has been established between necrosome and neuronal loss in the brains of clinical and preclinical patients with AD.…”

Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer disease

“…In addition to being a potent inflammatory cytokine, TNF-alpha is a powerful modulator of glutamate uptake, with TNF-alpha application to cultured astrocytes significantly reducing glutamate uptake (Ye and Sontheimer, 1996), at least in part through a downregulation of glutamate transporters (Zou and Crews, 2005). Importantly, TNF-alpha elevations are readily observed in the AD hippocampus (Jayaraman et al, 2021; Naghibi et al, 2021; Zhao et al, 2003). Therefore, it is possible that GLT-1 deficits promote the overactivation of astrocytic NMDARs, driving the release of TNF-alpha.…”