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, in response 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.

Inhibition of Neuronal Necroptosis Mediated by RIPK1 Provides Neuroprotective Effects on Hypoxia and Ischemia In Vitro and In Vivo

“…These data allow us to take a new look at the molecular pathogenetic pathways of hypoxic ischemic damage to nerve cells and consider RIP1 kinase as a potential therapeutic target for neuroprotection. There is also evidence of the important role of necroptosis in neurodegenerative processes in Alzheimer’s and Parkinson’s diseases, as well as in the development of secondary injuries in traumatic brain injury [ 7 , 21 ].…”

“…TNF binds to TNFR1 and TNFR2 receptors to activate a variety of cellular responses that can be neuroprotective or neurodegenerative. In particular, TNF can induce the activation of RIPK1 and downstream cascades and trigger necroptosis, although its significance in the loss of neurons in AD is still largely unstudied [ 21 ]; however, it opens another potential therapeutic aspect of the use of necroptosis inhibitors.…”

Alzheimer’s Disease: From Pathogenesis to Mesenchymal Stem Cell Therapy – Bridging the Missing Link

“…Necroptosis was found to be activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores (Caccamo et al, 2017). This necroptosis is likely linked to TNF (tumor necrosis factor) -mediated signaling pathway because increased expression of multiple proteins linked to TNF signaling pathway can be predominantly observed in the CA1 pyramidal neurons in the AD post-mortem brain (Jayaraman et al, 2021), accompanied by phosphorylation of RIPK3 and MLKL. These findings suggest targeting TNF-mediated necroptosis might be potential targets in AD pathogenesis.…”

“…Recently, necroptosis, a programed form of necrosis has been proven in postmortem human AD brains (Caccamo et al, 2017;Jayaraman et al, 2021). Unlike apoptosis, necroptosis is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3.…”

Pharmacological Effects of Gami-Yukmijihwang-Tang on the Lipopolysaccharide-Induced Hippocampus Oxidation and Inflammation via Regulation of Sirt6

“…Particularly, the hippocampus is the main target of pathogenesis AD among various regions of brain tissue [ 10 , 11 ] because this area plays a critical function for neuronal regeneration, also known as neurogenesis [ 12 ]. Numerous pathophysiological factors play a role in the pathological progression of neuroinflammation in complex ways in brain tissue, particularly the hippocampus regions [ 6 , 13 ]. During neuroinflammation, microglia cells are activated and infiltrated through the hippocampus regions, then they abnormally release pro-inflammatory cytokines including TNF-α, Il-1β, and Il-6, as well as oxidative stress mediators such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), respectively [ 14 , 15 , 16 , 17 , 18 , 19 ].…”