Table 2.

Mouse models of the NF-κB signaling pathway resembling ageing-associated human diseases.

NF-κB Gene	Genetic Modification	Recapitulated Disease and Proposed Mechanisms
		Eye Diseases
Ikkβ [87]	Specific knock-out of Ikkβ in astroglia. Use of the cre/loxP system under the regulation of the mouse glial Gfap to generate the GFAP-ikkβ mice.	Glaucoma GFAP-ikkβ mice lacking Ikkβ in astroglia show a high decrease in ocular hypertension and impeded inflammatory and neurodegenerative outcomes in the retina and optic nerve. This is the result of the inhibition of astroglial NF-κB activation, and decreased levels of proinflammatory cytokines in astroglia. Two- to three-month-old mice were analyzed.
Rela [89]	Generation of knock-in mice expressing the p65 S276D phosphomimetic protein, (p65PD mice), which show hyperactivation of NF-κB. Crossing of p65PD mice with mice deficient in Tnf receptor 1) to obtain the p65PD/Tnfrsf1a−/− mice.	Dry eye disease p65PD mice show a systemic hyperinflammatory condition due to increased TNF-α production, and died within 20 d after birth (5- and 10-day-old mice were studied). Crossing with Tnfr1 knockout mice rescues the phenotype, but aged p65PD/Tnfrsf1a−/− mice (3.5 to 8 months of age mice were analyzed) develop chronic keratitis or keratoconjunctivitis sicca (DED), with severe corneal epithelial lesions, marked neovascularization and inflammation of the corneal stroma, and increased levels of TNF-α, IL-1β, and MMP-9. DED chronic keratitis is independent of TNFR1 signaling but dependent on NF-κB.
		Neurodegenerative Diseases
c-Rel [93]	c-Rel gene null mutation generated by inserting the neomycin cassette into the fifth exon of the c-Rel gene.	Parkinson’s disease c-Rel KO mice develop PD-like neuropathology with ageing, manifested by age-dependent locomotor deficits reminiscent of bradykinesia and muscle rigidity. Loss of dopaminergic neurons, increased levels of iron and DMT1, and accumulation of aggregated α-synuclein with activation of microglial cells An altered balance between p65- and c-REL-mediated effects on neurons is proposed. Mice aged 2- to 18-month-old were analyzed.
c-Rel [92]	c-Rel gene null mutation generated by inserting the neomycin cassette into the fifth exon of the c-Rel gene.	Parkinson’s disease In addition to the phenotype described ([80]), c-Rel−/− mice show symptoms and pathology peculiar of prodromal syndrome and a Braak-like stereotyped diffusion of synucleinopathy mimicking sporadic Parkinson´s disease. Potential involvement of changes in levels of proteins controlling mitochondrial homeostasis, ROS generation and scavenging are proposed. Mice from 2 to 18 months of age were analyzed.
Iκbα [98]	NcKO mice: mice with CNS-specific Iκbα deletion (by crossingiIκbα flox with Nestin-Cre mice); CcKO and GcKO mice: mice with selective Iκbα deletion in neurons or in astrocytes, respectively (by crossing IkBa flox with CaMKIIa-Cre mice; or with GFAP-Cre mice).	Alzheimer´s disease This model links Amyloid β with synaptic defects and neuronal hyperexcitability though the sustained NF-κB activity in astrocytes, which results in the release of the complement protein C3 and the disruption of the dendritic morphology and network function characteristic of AD. Dysregulation of neuron-glia interaction through NF-κB/C3/C3aR signaling contribute to synaptic dysfunction in AD. Mice from 2 to 18 months of age were studied.
Iκbα [101]	Neuron-specific expression of IkBα super-repressor (IκBα-SR) driven by NFH neurofilament H promoter. Crosses of IκB-SR mice with familial ALS-linked mutant Tdp-43 (G348C and A315T) and Sod1 (G93A) mice.	Amyotrophic lateral sclerosis Mitigation of ALS symptoms and extension of life span in double transgenic mice IκBα-SR/TDP-43 and IκBα-SR/SOD1G93A mice. The inhibition of NF-κB activity by the expression of IκBα-SR in neurons alleviates TDP-43 in neuropathology through an induction of autophagy. Reduction of misfolded SOD1 levels in and IκBα-SR/SOD1G93A mice. Mice from 4 to 16 months of age were studied.
		Osteoporosis
Ikkβ [107]	Osteoprogenitor (OP)-specific, doxycycline-regulated Ikkβ-activated mouse model (iNF-κB/OP). These mice have activated NF-κB signaling in OP-lineage cells upon DOX withdrawal in skeletally mature mice.	iNF-κB/OP mice, with increased NF-κB activation in OP-lineage cells, showed reduced bone mineral density in the femurs and tibias and increased bone marrow fat, resembling human osteoporosis. The mechanisms involved are the decreased expression of osteogenic markers (Runx2 and osteocalcin) and the increased adipogenic markers (PPAR-γ and C/EBP) in mesenchymal stem cells (MSCs) of iNF-κB/OP mice. Mice of 12 and 36 weeks of age were analyzed.
		Osteoarthritis
Ikkα [111]	Aggrecan-driven cartilage-specific Ikkα KO mice in chondrocytes. cKO mice are treated with tamoxifen for the specific induction.	Wilt type (WT) and cKO underwent destabilization of the medial meniscus (DMM) surgery to induce OA. cKO mice are protected from cartilage degradation after surgical DMM. cKO mice showed both reduced cartilage degradation and collagenase activity. Mice from 12 to 24 weeks of age were studied.
		Muscle Diseases
Nfκb1 [116]	Nfκb1−/− and bcl3−/− mice.	Mice with KO of Nfκb1 or Bcl3 gene are resistant to muscle protein loss and functional deficit due to muscular disuse; they exhibit inhibition of fiber atrophy. Activation of the canonical pathway of NF-κB by TNF-α is associated with muscle protein loss.
Ikbα, c-Rel [118]	Expression of a dominant negative IκBα (IκBαΔN) in soleus muscles of rats (unloaded or weight bearing).c-Rel−/− mice are also used.	IκBαΔN expression in soleus muscles inhibits NF-κB activation and abolishes the unloading-induced increase in both NF-κB activation and total ubiquitinated protein, resulting in an inhibition of 40% fiber atrophy. The expression of genes upregulated in muscle atrophy is also inhibited (MAFbx/Atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, Cathepsin L).
Ikkβ [117]	IKKβmko mice exhibit muscle-specific NF-κB inhibition, through targeted deletion of Ikkβ. Muscle atrophy was induced by sciatic nerve denervation.	o mice, lacking NF-κB activation in muscle cells showed improved skeletal muscle strength and shifted muscle fiber distribution. In response to denervation, Ikkβ depletion protected against atrophy, maintaining fiber type, size, and strength, increasing protein synthesis (through the activation of protein synthetic pathways: AKT, GSK3α/β, mTOR, and p70S6K), and decreasing protein degradation (muscle RING finger 1 (MuRF1). Additionally, IKKβmko mice showed muscle regeneration after damage by enhanced satellite cell activation and reduced fibrosis.
Ikkβ [115]	Mice with specific expression of a constitutive kinase-active Ikkβ in Pax7-expressing satellite cells (inducible activation by Tamoxifen).	The selective activation of IKKβ in Pax7+ cells of transgenic mice led to an aggravated decline in muscle mass and fiber size. Overexpression of Pax7, induced by serum factors from cachectic mice in an NF-κB–dependent manner, was sufficient to induce atrophy in normal muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target, MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers.