Promising Intervention Approaches to Potentially Resolve Neuroinflammation And Steroid Hormones Alterations in Alzheimer's Disease and Its Neuropsychiatric Symptoms

Abstract

Neuroinflammation is a biological process by which the central nervous system responds to stimuli/injuries affecting its homeostasis. So far as this reactive response becomes exacerbated and uncontrolled, it can lead to neurodegeneration, compromising the cognitive and neuropsychiatric domains. Parallelly, modifications in the hypothalamic signaling of neuroprotective hormones linked also to the inflammatory responses of microglia and astrocytes can exacerbate these processes. To complicate the picture, modulations in the gut microbiota (GM) can induce changes in neuroinflammation, altering cognitive and neuropsychiatric functioning. We conducted a web-based search on PubMed. We described studies regarding the cross-talk among microglia and astrocytes in the neuroinflammation processes, along with the role played by the steroid hormones, and how this can reflect on cognitive decline/neurodegeneration, in particular on Alzheimer's Disease (AD) and its neuropsychiatric manifestations. We propose and support the huge literature showing the potentiality of complementary/alternative therapeutic approaches (nutraceuticals) targeting the sustained inflammatory response, the dysregulation of hypothalamic system and the GM composition. NF-κB and Keap1/Nrf2 are the main molecular targets on which a list of nutraceuticals can modulate the altered processes. Since there are some limitations, we propose a new intervention natural treatment in terms of Oxygen-ozone (O2-O3) therapy that could be potentially used for AD pathology. Through a meta-analytic approach, we found a significant modulation of O3 on inflammation-NF-κB/NLRP3 inflammasome/Toll-Like Receptor 4 (TLR4)/Interleukin IL-17α signalling, reducing mRNA (p<0.00001 Odd Ratio (OR)=-5.25 95% CI:-7.04/-3.46) and protein (p<0.00001 OR=-4.85 95%CI:-6.89/-2.81) levels, as well as on Keap1/Nrf2 pathway. Through anti-inflammatory, immune, and steroid hormones modulation and anti-microbial activities, O3 at mild therapeutic concentrations potentiated with nutraceuticals and GM regulators could determine combinatorial effects impacting on cognitive and neurodegenerative domains, neuroinflammation and neuroendocrine signalling, directly or indirectly through the mediation of GM.

Keywords: Alzheimer’s Disease; Keap1/Nrf2; NF-κB; Neuroinflammation; Nutraceuticals; Oxygen-Ozone Therapy; Steroid hormones.

Conflict of interest statement

Conflicts of interest The authors declare no conflict of interest.

copyright: © 2021 Scassellati et al.

Figures

Figure 1.

Neuroinflammation, steroid hormones alteration and gut microbiota (GM) modulation in Alzheimer Disease (AD) and its neuropsychiatric symptoms. We illustrate three crucial features underlying the neurodegenerative disorders such as AD and its neuropsychiatric manifestations (Behavioral and psychological symptoms of dementia, BPSD): a) chronic neuroinflammation and the complex interplay between astroglia and microglia, b) alterations in the hypothalamic signalling of neuroprotective hormones linked also to the inflammatory responses of microglia and astrocytes, and c) modulations in the GM, inducing changes in brain activities contributing to neuroinflammation, and altering cognitive and neuropsychiatric functioning. Tumour necrosis factor-α (TNF-α); Interleukin (IL)-1β; IL-6; prostaglandins (PGs); nitric oxide (NO); Reactive oxygen species (ROS); Toll-like receptors (TLRs); Nuclear factor Nf-κB; Activator protein 1 (AP-1); Receptor for advanced glycation endproducts (RAGE); Glycoprotein 130 (gp130); Neurotrophic Receptor Tyrosine Kinase 2 (TRKB-T1); Smad interacting protein 1 (SIP1); Translocator protein (TSPO); PREG (Pregnenolone); Dehydroepiandrosterone (DHEA); Progesterone (PROG).

Figure 2.

The potential positive effects of Oxygen-Ozone O2-O3 therapy and Gut Microbiota Regulators (GRMs) on gut microbiota (GM) and consequently on neuroinflammation and neuroendocrine system. We illustrate how a natural bio molecule such as Ozone (O3) showing immune, anti-inflammatory, anti-microbial properties with effects on glucocorticoids (GCs), could represent a new treatment to delay neuroinflammation/neurodegeneration in Alzheimer Disease (AD), where the balance between pro-anti-inflammatory system and the hypothalamic signalling and GM composition are impaired. Moreover, we illustrate that the supplementation of GRMs in terms of Probiotics and GV-971, already used for AD, can potentiate the O3 activities, determining combinatorial effects that could impact on cognitive and neuropsychiatric domains, neuroinflammation and hypothalamic signalling, directly or indirectly through the mediation of GM.

Figure 3.

Mechanisms of action of Nutraceuticals (Ns) and Ozone (O3) on NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells)/Keap1 (kelch-like ECH-associated protein)/Nrf2 (nuclear factor erythroid 2-related factor 2) molecular pathways. Here, we illustrate how NF-κB and Keap1/Nrf2 signalling pathways involved in the neuroinflammation/neurodegeneration in Alzheimer’s Disease mechanisms can be therapeutic targets for Nutraceuticals (Ns) and Ozone (O3) molecule. In the absence of stimuli, NF-κB is found in cytoplasm bound to the inhibitory IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor) proteins. In response to stimuli (Reactive oxygen species, ROS), IκB proteins are rapidly phosphorylated by IκB kinase and ultimately degraded by the 26S proteasome. The resulting release of NF-κB and subsequent translocation to the nucleus promote its action on target genes involved in inflammation/immunity (pro-inflammatory cytokines). If chronic, this can provoke neuroinflammation/neurodegeneration. O3 (by second messengers: Hydrogen Peroxide, H2O2 and 4-Hydroxynonenal, 4HNE) and Ns can block this system, contributing to an anti-inflammatory response. On the other hand, the Keap1/Nrf2 pathway is organized in this way: in the absence of stimuli, Nrf2 binds to its repressor Keap1, an adapter between Nrf2 and Cullin 3 protein, which leads to ubiquitination followed by proteasome degradation. Under oxidative stress, after heterodimerization with the Muscoloaponeurotic Fibrosarcoma (MAFs), the Nrf2 translocates to the nucleus, where it dimerizes and binds to ARE (Antioxidant Response Element) genes: Superoxide dismutase (SOD), Glutathione (GSH), Glutathione-S-Transferase (GST), Glutamate-cysteine ligase (GCL), heme oxygenase 1 (HO-1), NADPH:quinone oxidoreductase 1 (NQO1), and other anti-oxidant enzymes, provoking a strong anti-oxidant response. HO-1 is a gene encoding enzyme that catalyses the degradation of heme in carbon monoxide (CO), that in turn is an inhibitor of the NF-κB pathway, thereby decreasing the expression of pro-inflammatory cytokines. HO-1 directly inhibits the pro-inflammatory cytokines and activates the anti-inflammatory cytokines. Keap1 can also prevents NF-κB activity via IKK (IκB kinase) inhibition. O3 (by second messengers: Hydrogen Peroxide, H2O2 and 4-Hydroxynonenal, 4HNE) and Ns can activate Keap1/Nrf2 signalling exercising both anti-inflammatory and anti-oxidant effects. O3 and Ns can activate pro-autophagy and anti-apoptosis mechanisms and block proteosome degradation. Ns can have significant effects on Aβ and τ toxicity and aggregation, decreasing the neurodegeneration.

Figure 4.

Forest plot for odds ratio (OR) from meta-analysis of the inflammation-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)/NLRP3 inflammasome/Toll-Like Receptor 4 (TLR4)/Interleukin IL-17α signalling (mRNA genes expression) before and after ozone (O3) treatment. CI, confidence interval; Chi2, χ2 test of goodness of fit; Tau2, estimate of the between-study variance in a random-effects meta-analysis.

Figure 5.

Forest plot for odds ratio (OR) from meta-analysis of the inflammation-NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)/NLRP3 inflammasome/Toll-Like Receptor 4 (TLR4)/Interleukin IL-17α signalling (protein levels) before and after ozone (O3) treatment. CI, confidence interval; Chi2, χ2 test of goodness of fit; Tau2, estimate of the between-study variance in a random-effects meta-analysis.