Sustained, neuron-specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging

Abstract

BackgroundIncreasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively active allele of IKK2 in principal forebrain neurons (IKK2nCA). Proinflammatory gene and growth factor expression, histopathology, microgliosis, astrogliosis, immune cell infiltration and spatial learning were assessed at different timepoints after persistent canonical IKK2/NF-κB activation.ResultsIn contrast to other cell types and organ systems, chronic IKK2/NF-κB signalling in forebrain neurons of adult IKK2nCA animals did not cause a full-blown inflammatory response including infiltration of immune cells. Instead, we found a selective inflammatory response in the dentate gyrus characterized by astrogliosis, microgliosis and Tnf-α upregulation. Furthermore, downregulation of the neurotrophic factor Bdnf correlated with a selective and progressive atrophy of the dentate gyrus and a decline in hippocampus-dependent spatial learning. Neuronal degeneration was associated with increased Fluoro-jade staining, but lacked activation of apoptosis. Remarkably, neuronal loss could be partially reversed when chronic IKK2/NF-κB signalling was turned off and Bdnf expression was restored.ConclusionOur results demonstrate that persistent IKK2/NF-κB signalling in forebrain neurons does not induce overall neuroinflammation, but elicits a selective inflammatory response in the dentate gyrus accompanied by decreased neuronal survival and impaired learning and memory. Our findings further suggest that chronic activation of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis.

Vanillic acid attenuates Aβ1-42-induced oxidative stress and cognitive impairment in mice

“…demonstrated that activated IKK-β/NF-κB-induced neuroinflammation promotes neurodegeneration during aging. In this study, we investigated whether Aβ 1-42 increased the expression of IKK-β/NF-κB, which can trigger other inflammatory mediators66. Vanillic acid treatment reversed the Aβ 1-42 -induced elevated expression of IKK-β/NF-κB and reduced the activity of IKKβ/NF-κB.…”

Microglia activation due to obesity programs metabolic failure leading to type two diabetes

“…80 However, aberrant activation of the IKK/NF-κB axis has been linked to selective neuroinflammation and apoptosis independent of neurodegeneraion. 81 In the context of metabolic damage, it has been shown that inhibition of the IKK/NF-κB axis using the terpenoid (Rb1) reduces inflammation and leptin resistance in the hypothalamus. 82 Furthermore, it has also been shown that lipotoxicity activates the proinflammatory axis IKKβ-NF-κB in the hypothalamus, promoting the generation of insulin resistance.…”

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

“…Studies of the central actions of IKKβ have concentrated on neurodegenerative or metabolic disorders, but did not involve ethanol exposure (Zhang et al, 2008; Maqbool et al, 2013). Other studies have shown that IKKβ gene expression was altered in postmortem prefrontal cortex (PFC) from alcoholic individuals (Flatscher-Bader et al, 2005) and mouse PFC following ethanol exposure and in selectively bred animals predisposed to drink alcohol (Mulligan et al, 2006; Osterndorff-Kahanek et al, 2015).…”