Nuclear factor κB activation impairs ependymal ciliogenesis and links neuroinflammation to hydrocephalus formation.

Hydrocephalus formation is a frequent complication of neuropathological insults associated with neuroinflammation. However, the mechanistic role of neuroinflammation in hydrocephalus development is unclear. We have investigated the function of the proinflammatory acting inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling system in neuroinflammatory processes and generated a novel mouse model that allows conditional activation of the IKK/NF-κB system in astrocytes. Remarkably, NF-κB activation in astrocytes during early postnatal life results in hydrocephalus formation and additional defects in brain development. NF-κB activation causes global neuroinflammation characterized by a strong, astrocyte-specific expression of proinflammatory NF-κB target genes as well as a massive infiltration and activation of macrophages. In this animal model, hydrocephalus formation is specifically induced during a critical time period of early postnatal development, in which IKK/NF-κB-induced neuroinflammation interferes with ependymal ciliogenesis. Our findings demonstrate for the first time that IKK/NF-κB activation is sufficient to induce hydrocephalus formation and provides a potential mechanistic explanation for the frequent association of neuroinflammation and hydrocephalus formation during brain development, namely impairment of ependymal cilia formation. Therefore, our study might open up new perspectives for the treatment of certain types of neonatal and childhood hydrocephalus associated with hemorrhages and infections.

IκB kinase/nuclear factor κB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling.

Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF-κB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase (IKK)/NF-κB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF-κB-dependent synapse development and remodeling. Here, we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmission and a spatial learning impairment. Synaptic deficits can be restored in adult animals within 1 week by IKK/NF-κB reactivation, indicating a highly dynamic IKK/NF-κB-dependent regulation process. We further identified the insulin-like growth factor 2 gene (Igf2) as a novel IKK/NF-κB target. Exogenous Igf2 was able to restore synapse density and promoted spine maturation in IKK/NF-κB signaling-deficient neurons within 24 h. This process depends on Igf2/Igf2R-mediated MEK/ERK activation. Our findings illustrate a fundamental role of IKK/NF-κB-Igf2-Igf2R signaling in synapse formation and maturation in adult mice, thus providing an intriguing link between the molecular actions of IKK/NF-κB in neurons and the memory enhancement factor Igf2.

Targeted isolation of photoactive pigments from mushrooms yielded a highly potent new photosensitizer: 7,7'-biphyscion.

Pigments of fungi are a fertile ground of inspiration: they spread across various chemical backbones, absorption ranges, and bioactivities. However, basidiomycetes with strikingly colored fruiting bodies have never been explored as agents for photodynamic therapy (PDT), even though known photoactive compound classes (e.g., anthraquinones or alkaloids) are used as chemotaxonomic markers. In this study, we tested the hypothesis that the dyes of skin-heads (dermocyboid Cortinarii) can produce singlet oxygen under irradiation and thus are natural photosensitizers. Three photosensitizers based on anthraquinone structures were isolated and photopharmaceutical tests were conducted. For one of the three, i.e., (-)-7,7'-biphyscion (1), a promising photoyield and photocytotoxicity of EC50 = 0.064 µM against cancer cells (A549) was found under blue light irradiation (λexc = 468 nm, 9.3 J/cm2). The results of molecular biological methods, e.g., a viability assay and a cell cycle analysis, demonstrated the harmlessness of 1 in the dark and highlighted the apoptosis-inducing PDT potential under blue light irradiation. These results demonstrate for the first time that pigments of dermocyboid Cortinarii possess a so far undescribed activity, i.e., photoactivity, with significant potential for the field of PDT. The dimeric anthraquinone (-)-7,7'-biphyscion (1) was identified as a promising natural photosensitizer.

IKK2/NF-κB Activation in Astrocytes Reduces amyloid ß Deposition: A Process Associated with Specific Microglia Polarization.

Alzheimer's disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number of amyloid plaques in the cerebral cortex and hippocampus. Interestingly, isolated primary astrocytes and microglia cells exhibit specific marker gene profiles which, in the case of microglia, point to an enhanced plaque clearance capacity. In contrast, direct IKK2/NF-κB activation in microglia results in a pro-inflammatory polarization program. Our findings suggest that IKK2/NF-κB signaling in astrocytes may activate paracrine mechanisms acting on microglia function but also on APP processing in neurons.

Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration.

BACKGROUND: Neuroinflammation is associated with a wide range of neurodegenerative disorders, however the specific contribution to individual disease pathogenesis and selective neuronal cell death is not well understood. Inflammatory cerebellar ataxias are neurodegenerative diseases occurring in various autoimmune/inflammatory conditions, e.g. paraneoplastic syndromes. However, how inflammatory insults can cause selective cerebellar neurodegeneration in the context of these diseases remains open, and appropriate animal models are lacking. A key regulator of neuroinflammatory processes is the NF-κB signalling pathway, which is activated by the IκB kinase 2 (IKK2) in response to various pathological conditions. Importantly, its activation is sufficient to initiate neuroinflammation on its own. METHODS: To investigate the contribution of IKK/NF-κB-mediated neuroinflammation to neurodegeneration, we established conditional mouse models of cerebellar neuroinflammation, which depend either on the tetracycline-regulated expression of IKK2 in astrocytes or Cre-recombination based IKK2 activation in Bergmann glia. RESULTS: We demonstrate that IKK2 activation for a limited time interval in astrocytes is sufficient to induce neuroinflammation, astrogliosis and loss of Purkinje neurons, resembling the pathogenesis of inflammatory cerebellar ataxias. We identified IKK2-driven irreversible dysfunction of Bergmann glia as critical pathogenic event resulting in Purkinje cell loss. This was independent of Lipocalin 2, an acute phase protein secreted by reactive astrocytes and well known to mediate neurotoxicity. Instead, downregulation of the glutamate transporters EAAT1 and EAAT2 and ultrastructural alterations suggest an excitotoxic mechanism of Purkinje cell degeneration. CONCLUSIONS: Our results suggest a novel pathogenic mechanism how diverse inflammatory insults can cause inflammation/autoimmune-associated cerebellar ataxias. Disease-mediated elevation of danger signals like TLR ligands and inflammatory cytokines in the cerebellum activates IKK2/NF-κB signalling in astrocytes, which as a consequence triggers astrogliosis-like activation of Bergmann glia and subsequent non-cell-autonomous Purkinje cell degeneration. Notably, the identified hit and run mechanism indicates only an early window for therapeutic interventions.