Overexpression of the amyloid precursor protein (APP) gene is associated with familial aggregation of late onset AD and dramatically increases susceptibility to early AD in Down’s syndrome. APP is cleaved by the beta-secreatase BACE1 into amyloid monomers that form oligomers that eventually become plaques in the brain and vasculature. Both BACE1 and NF-κB are increased in the brains of AD patients, with NF-κB directly upregulating BACE1 and the APP gene (27, 28). Medications such as minocycline, that inhibit NF-κB but not BACE1 or APP, reverse this process (28, 29).

The e4 variant of the APOE gene, which codes for a cholesterol transporting protein, is the largest, single gene risk factor for AD (30). In APOE e4-positive Schwann cell lines, when compared to APOE e3-expressing cells, excess production of IL6, IL10, and nitrous oxide results from a failure to inhibit NF-κB (31). These findings are replicated in neural cells and fibroblasts from AD patients where APOE e4 acts as a transcription factor responsible for regulating NF-κB expression (32). Curiously, cells from the somatosensory cortex of AD patients, an area of the brain that is resistant to disease, display upregulation of NF-κB (33). However, this may reflect the earliest inflammatory hallmark of disease as previous autopsy studies have shown increased NF-κB activation in evolving Aβ deposits with a reduction in areas surrounding more mature plaques (19, 33).

A genetic screen for dominant suppressors and enhancers in a Drosophila model of Aβ-driven neurodegeneration revealed that Toll gene (receptor of Drosophila toll pathway) and key downstream components (dif, pelle, cactus), play a central role in mediating the neuropathological activities (34). Conversely, genetic overexpression results in accelerated deterioration of the phenotype suggesting that NF-κB significantly enhances the pathological potential of Aβ (35).

Genetic suppression of the immune deficiency (IMD) NF-κB pathway in glial cells in a Drosophila model of early onset neurodegeneration dramatically rescues brain pathology, reduced activity, and short lifespan (13). Genetic overexpression of NF-κB pathways at neuronal or glial tissue level leads to phenotypes resembling AD models with locomotor disability, accelerated neurodegeneration, and premature mortality (13).

Age is the biggest risk factor for dementia and systemic inflammation increases as animal’s age, a process known as inflammaging (36). Microglia priming in mice induces a highly conserved transcriptional signature with aging characterized by NF-κB expression and neuronal death (37). In rats, NF-κB expression increases in normal aging leading to production of neurodegenerative pro-inflammatory enzymes COX-2 and iNOS (38). These changes are reversed by suppression of brain NF-κB activation using the anti-inflammatory Lactobacillus pentosus var. plantarum C29, restoring brain-derived neurotrophic factor (BDNF) levels and memory (39). In mice, the observed positive correlation between NF-κB activity and neuronal apoptosis suggests a role of NF-κB in hippocampal neuroapoptosis (40). Supporting this, NF-κB induces pro-apoptotic increases in TNF and iNOS in the hippocampus of rats exposed to neurotoxin (41).

Inactivating specific Sirtuin anti-aging genes in mice results in chronic NF-κB overexpression leading to accelerated aging and dramatically reduced lifespan (23). In Sirtuin replete models, overexpression via biofeedback dysregulation results in premature aging through chronic production of excessive ROS, leading to telomere dysfunction, cellular senescence, and premature death (42). Age-related NF-κB activation feeds into a positive feedback loop in microglial cells causing perpetual inflammation and multiple brain responses including epigenetic suppression of GnRH genes in the hypothalamus (14). Microglial-derived NF-κB-TNF-α axis plays a key role in homeostatic synaptic scaling, a form of synaptic plasticity. However, overexpression results in disrupted neuronal networks and behavior mimicking obsessive–compulsive disorder (OCD) (43, 44). Suppressing this pathway mediates some of the OCD-like behavioral problems in mouse models of frontotemporal dementia (44). Specifically, under-expression of NF-κB in the mouse brain results in delayed onset of age-related pathology across all organ systems via preservation of the hypothalamic–pituitary–adrenal axis and GnRH levels (14).

Type 2 diabetes mellitus (T2DM), a metabolic condition characterized by a decrease in sensitivity to endogenous insulin, is the best established environmental risk factor for the development of AD, increasing relative risk by 50% (45). Diabetes induces Aβ pathology via NF-κB upregulation and independent overexpression of BACE1 (46, 47). Inflammatory mediators are known to contribute to insulin resistance creating a pro-inflammatory feedback loop in diabetes (48). Administering advanced glycation end products that mimic diabetic driven pathology results in elevated BACE1 and consequent NF-κB overexpression in both rat brains in vivo and neuroblastoma cells lines (49). NF-κB suppression using Adiponectin rescues Aβ pathology in human T2DM neuroblastoma cells (50). Similarly, leukotriene D4, an inflammatory signaling molecule elevated in metabolic disorders, induces Aβ synthesis in primary neurons at 24 h with increases in NF-κB seen after just 1 h (51, 52). Treatment of the culture with NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) inhibited Aβ generation with down regulation of Aβ generating beta- and gamma-secretase activity suggesting NF-κB regulates Aβ synthesis in metabolic disease (52).

In human neuroblastoma cells, the metabolic enzyme protein arginine methyltransferase 5 (PRMT5) regulates cellular metabolism, protecting the cell in times of stress. Aβ downregulates this process leading to NF-κB overexpression, metabolic dysfunction, and premature cell death (53). Inhibiting NF-κB reduces apoptosis and Aβ deposits even in a metabolically dysfunctional organism or human cell lines suggesting a gatekeeper role for NF-κB in maintaining metabolic homeostasis and subsequent neuroprotection independent of PRMT5 activity (53).

In Drosophila models of chronic diseases including AD, the innate immune system has been identified as a key mediator of neurodegeneration (13, 34, 54, 55). NF-κB overexpression in the fat body cells, analogous to the metabolic syndrome in humans, results in more severe neurodegeneration (56).

Supporting the role of NF-κB in connecting whole-body metabolism with brain health, NF-κB overexpression in the hypothalamus-like pars intercerebralis neurons in Drosophila results in overnutrition, impaired metabolic learning, poor memory consolidation, and metabolic disorder characterized by increased lipid levels and shortened lifespan (57). Conversely, genetic knockdown of NF-κB signaling in glial cells leads to elevated adipokinetic and glucagon-like hormone levels, reduced glucose and lipid levels, and extension of “healthspan” (13).

In rodent and primate models, diabetes and obesity drive overexpression of NF-κB in the hypothalamus creating a destructive feedback loop where further NF-κB expression promotes hypertension, overnutrition, and decreased insulin sensitivity (58–61). Injecting Aβ into the brains of mice and macaques results in an increase in NF-κB in the cell nuclei of the hypothalamus and subsequent induction of peripheral glucose intolerance (62). In this model, pharmacological inhibition of NF-κB maintained peripheral metabolic homeostasis. Inducing diabetes in rats results in hippocampal NF-κB-dependent neurodegeneration via disruption of CREB phosphorylation, reducing levels of protective downstream proteins including BDNF (63).

The tetracycline derivative Minocycline inhibits NF-κB and prevents further Aβ deposition in a mouse model of diabetes-driven AD. BACE1 activity remained elevated demonstrating an NF-κB-dependent protective mechanism (29). Mice fed on high-fat diets demonstrate elevated brain BACE1 expression as do transgenic diabetic mice. Administration of the anti-inflammatory agent all-trans-retinoic acid reduces BACE1 expression in both WT and mutant but this effect is abolished when the NF-κB-binding site at the promoter region of BACE1 is mutated (64).

In Drosophila, alcohol consumption activates Toll-NF-κB signaling increasing ethanol resistance and gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure (65). Ethanol treatment of cultured hippocampal rat neurons causes a dose- and time-dependent increase in NF-κB-DNA-binding activity, resulting in significant upregulation of inflammatory markers and increased susceptibility to neurotoxins; reversible by applying NF-κB inhibitors (66, 67).

Opposing, the consumption of moderate amounts of alcohol, particularly red wine, is associated with a reduced risk of AD. Anthocyanin, a polyphenol found in wines, protects rat hippocampal neurons against oxidative stress via NF-κB suppression (41, 68).

Sleep quality and well-being are symbiotic and reduced sleep quality is increasingly being associated with increased risk of dementia. Sleep–wake cycle homeostasis is important in the processing and removal of Aβ plaques which, in turn, are known to dysregulate this reparative process (69). Sleep disruption and deprivation are known to cause over expression of the NF-κB pathway in hippocampal cell cultures, fruit flies, rodents, and humans (70–73). Improvement in sleep quality in older adults is correlated with a reduction in circulating NF-κB (74).

Traumatic brain injury activates both microglia and astrocytes and induces self-sustaining inflammatory responses in the brain via NF-κB activation (75, 76). In Drosophila, flies with TBI exhibited temporary incapacitation, ataxia, activation of the innate immune response, neurodegeneration, and death similar to humans with TBI (77, 78). Rat models have demonstrated the acute onset and prolonged overexpression of NF-κB in brain regions most commonly associated with post-injury atrophy (79, 80). Recent studies have shown NF-κB to be significantly elevated in the ipsi-lateral cortex of both adult and old TBI mice in a time-dependent manner (81). These interactions started immediately post-injury in the old mice compared to the adult mice suggesting an age-related failure of NF-κB suppression.

Under expressing NF-κB in mice results in greater endurance, cognitive performance, and resistance to obesity (82). An aerobic exercise protocol in wild-type rats attenuated age-related memory decline and decreased hippocampal NF-κB levels and atrophy (83). In rats fed a pro-inflammatory diet and subjected to either strength training, aerobic exercise or a combination of both, all protocols reduced liver and muscle NF-κB levels to pre-diet levels (84). These findings are supported by studies demonstrating the indirect suppression of NF-κB via cytokine IL-10, a potent NF-κB inhibitor, induced by exercise (85).

Curcumin, a constituent of turmeric, has gained much attention in recent years for its potential as a neuroprotective compound. In a Drosophila model of neurodegeneration, the curcumin analog C150 significantly reduced neuronal cell death, increased healthy lifespan, and reduced DNA mutation in brain tissue by suppressing NF-κB (86).

The neuroprotective effects resulting from the Mediterranean diet or those rich in oily fish may be mediated via the anti-inflammatory properties of key nutrients (87). Aβ induced increases in the translocation NF-κB subunits is attenuated in the presence of tyrosol (Tyr) and hydroxytyrosol (OH-Tyr) found abundantly in olive oil (88). Transgenic increases in omega-3 polyunsaturated fatty acid in the brain of mice reduces the inflammatory response to LPS challenge via NF-κB pathways (89).

The omega 3 fatty acid eicosapentaenoic acid indirectly downregulates NF-κB expression acting as a ligand at peroxisome proliferator-activated receptor gamma, a regulator of fatty acid storage and glucose metabolism, and reduces symptoms of depression (87, 90). In AD-mouse hippocampal slices, food-derived anti-oxidants provide neuroprotection and reduce Aβ via the anti-inflammatory properties of the polyphenolic compounds within them (91). Specifically, the phenolic compound resveratrol reduces Aβ-induced migroglial activity and neuroinflammation via NF-κB suppression in murine microglial and macrophage cells (92).

The prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction in the AD risk (93). In primary rat, neurons and human neuronal cell lines NSAIDs strongly inhibit NF-κB-driven expression of BACE1 activity preventing the cleavage of Aβ from APP (28, 94). Long-term administration of potent NSAID indomethacin blocks activation of NF-κB and significantly reduced the amyloid pathology in transgenic AD mice (95).

Aspirin, an NSAID derived from salicylic acid, completely inhibits Aβ activation of the NF-κB pathway, reducing levels of pro-inflammatory cytokines and chemokines, and increasing levels of anti-inflammatory IL-10 in rodent microglia and neurons resulting in recruitment of Aβ phagocytic microglia and improved cognitive and synaptic functioning (28, 96).