title: Sustained, neuron-specific IKK/NF-κB activation generates a selective neuroinflammatory response promoting local neurodegeneration with aging.
abstract: BACKGROUND
  Increasing 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, Ulm 89081 Germany. bernd.baumann@uni-ulm.de.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Maqbool
authors.forename: Michael
authors.initials: M
authors.lastname: Lattke
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse