NT-020 treatment reduces inflammation and augments Nrf-2 and Wnt signaling in aged rats
- Antwoine Flowers†1,
- Jea-Young Lee†1,
- Sandra Acosta1,
- Charles Hudson2,
- Brent Small3,
- Cyndy D. Sanberg4,
- Paula C. Bickford1, 2Email author and
- Bethany Grimmig1
© Flowers et al. 2016
Received: 2 September 2015
Accepted: 9 September 2015
Published: 17 September 2015
The Erratum to this article has been published in Journal of Neuroinflammation 2016 13:229
Aging is associated with a decline in stem cell proliferation that is thought to be a result of dysregulated signaling in the neurogenic niche. This results in a diminished and less efficient pool of progenitors. The Wnt pathway plays a key role in the proliferation and differentiation of progenitor cells. Recent publications suggest that the age-related decline in the function of Wnt is a contributor to age-dependent decline in neural progenitors. Similarly, the aged neurogenic niche is characterized by higher levels of inflammatory cytokines. This increased inflammation contributes to the declining function of neural progenitor cells. NT-020, a proprietary blend of polyphenols, has been shown to increase proliferation of neural progenitors and improve cognitive function in aged rats.
Purpose and methods
In this study, we examined the neurogenic niche in the subgranular zone of the dentate gyrus (SGZ) and the subventricular zone (SVZ) of young and aged rats to determine if dietary supplementation with NT-020 could regulate inflammation and oxidative stress response pathways in neurons, astrocytes, and microglia. Further, we examined NT-020’s ability to modulate Wnt signaling in the aged neurogenic niche. To accomplish this, we utilized gene PCR arrays and immunohistochemistry.
We observed an increase in nuclear localization of immunopositive labeling of β-catenin, HO-1, and Nrf2 in all subsets of cell types in both young and aged rats in the SGZ and SVZ following NT-020 treatment. NeuN-positive cells showed a basal increase in nuclear β-catenin in the aged rats, which was not observed in doublecortin (DCX)-labeled cells, microglia, or astrocytes. Reverse transcription polymerase chain reaction (RT-PCR) analysis of isolated hippocampal tissue revealed that a significant percent of genes involved with inflammation are affected by treatment with NT-020. In addition, several genes that regulate Wnt activity were affected by supplementation.
The results suggest that NT-020 activates oxidative stress response pathways and supports pro-neurogenic gene expression in the hippocampus. This may represent the mechanism by which the NT-020 formula enhances performance in learning and memory tasks in aged mice.
As the world’s aging population increases, diseases that disproportionately affect the elderly will take center stage in biomedical research. In addition to increasing disease risk, aging can have deleterious effects on neural plasticity. Impairments in long-term potentiation (LTP), declines in neurogenesis, and synapse dysfunction are observed in the aged hippocampus [1–4]. Interestingly, most of these age-dependent changes overlap with known effects of pro-inflammatory cytokine expression (see reviews [5, 6]). Neuroinflammation is a central component of the aging milieu and contributes to the progression of a number of degenerative diseases, see review . Polyphenolic compounds have shown promise in addressing several aspects of aging including synaptic dysfunction, decreased neurogenesis, and inflammation [8–10]. Here, we demonstrate that a proprietary blend of polyphenolic compounds attenuates inflammatory cytokine expression and enhances pro-neurogenic signaling in the hippocampus.
The hippocampus is unique in its anatomy as it is one of only two areas in the adult brain with an extensive stem cell niche . The role of adult neurogenesis in the formation of new memories and enhancement of learning has been extensively studied over the last decade [2, 12, 13]. One of the major regulators of adult neurogenesis is the Wnt/β-catenin pathway . Proper Wnt signaling is crucial for progenitor proliferation, differentiation, and integration into the granule layer, see review [15–17]. Pathological alterations in Wnt signaling can result in impairments of neurogenesis and behavioral deficits [17, 18]. In addition, Wnt ligands are known to decrease in the aged hippocampus, replacement of which is sufficient to rescue proliferation of neural progenitors in mouse models [17, 19]. While it has been demonstrated that polyphenols like epigallocatechin gallate (EGCG) are capable of enhancing neurogenesis in vivo, no mechanism for this action has yet been proposed. Here, we investigate the interaction between polyphenolic compounds and the Wnt/β-catenin pathway as a possible mechanism by which neurogenesis is enhanced in these models.
The aged hippocampus contains an increased number of activated astrocytes and microglia, as well as increased levels of pro-inflammatory cytokines such as TNF-α and IL-1β . High levels of TNF-α and IL-1β have deleterious effects on neurogenesis, LTP, and synaptic formation . Genomic and proteomic profiles of aged immune cells from the brain have yet to reveal a definitive cause for these changes, but several studies suggest that oxidative stress caused by mitochondrial dysfunction may be a primary contributor [20, 21]. Polyphenols have been shown to have a wide range of neuro-protective effects and may exert their action through modulation of immune cells adaptive stress response system [9, 22]. The nuclear factor erythroid 2-related factor 2 antioxidant response element (Nrf2-ARE) pathway is involved in the cellular response to oxidative stress and leads to the transcription of several antioxidant genes . Loss of Nrf2 increases microglial activation and leads to a primed phenotype similar to that observed with aging [24, 25]. In addition, overexpression of Nrf2 is sufficient to attenuate NF-κB signaling and reduce inflammatory responses . Upregulation of Nrf2-ARE may be a central mechanism by which polyphenols attenuate inflammation .
In this manuscript, we utilized PCR arrays and the bioinformatics program Ingenuity Pathway Analysis (IPA) to study the age-dependent changes in the Wnt signaling pathway and expression of cytokines in the hippocampus. We show here that treatment of aged mice with the NT-020 formula decreases expression of inflammatory cytokines, increases expression of anti-inflammatory cytokines and trophic factors, and decreases several antagonists of Wnt signaling. We conclude that dietary supplementation with this formula is sufficient to attenuate the neuro-inflammatory component of aging.
Materials and methods
Animals and procedures
Male Fischer 344 rats either young 3 months or 20 months of age were randomly segregated into two groups; one was fed an NIH31 control diet and the experimental group was fed a modified diet which included the NT-020 formulation at 135 mg/kg for 30 days. On day 30, rats were anesthetized deeply with isoflurane gas before euthanasia. All rats were divided into two groups. One group was used for tissue, the hippocampus was removed and used for RNA isolation. Another group was perfused intracardially with 0.1M PBS followed by 4 % paraformaldehyde in 0.1 M phosphate buffer saline and sacrificed; the brain was removed and used for immunohistochemistry. All procedures involving animals were approved by the USF/VA IACUC committee; approved protocol # 4389V.
Real-time reverse transcription polymerase chain reaction
Tissues were removed and microdissected to isolate the hippocampus. Samples were snap frozen in liquid nitrogen and stored at −80 °C until homogenization. Total RNA was isolated from tissue of adult rat hippocampus using RNeasy mini kit (Qiagen, Valencia, CA, USA). Quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed using DNA Engine Opticon 2© (Bio-rad Hercules, CA) with multi-stage program parameters as follows: 10 min at 95 °C, 40 cycles of 15 s at 95 °C, and 1 min at 60 °C. Samples were tested in triplicate, and the samples obtained from three to five independent tissues were used for the analysis of relative gene expression using the 2 − ΔΔCT method. The following PCR arrays were utilized for this study: WNT signaling targets array PARN-243Z, and cytokine and chemokine array PARN-150Z (Qiagen, Valencia, CA). These arrays contain primers corresponding to 84 genes related to the individual pathways, five housekeeping genes for normalization, and positive and negative controls for the PCR reaction. Genes were considered to be differentially expressed if their expression differed by at least twofold between the young and old or old and old supplemented groups, and that difference was statistically significant across replicates, p < 0.05.
Immunohistochemistry and analysis
Immunohistochemistry was used to identify nuclear labeling of Nrf2 or β-catenin in either neurons (NeuN), microglia (IBA-1), astrocytes (GFAP), or neuronal progenitors (doublecortin (DCX)) observed in young and aged F344 rat brain. The primary antibodies (1:500) were polyclonal antibodies raised in rabbit against NeuN, GFAP, DCX (Abcam), and IBA-1 (Waco) and monoclonal antibodies raised in mouse against β-catenin, Nrf2, or HO-1 (Abcam) with blocking buffer (TritonX-100 (0.02 %), normal goat serum (4 %)). The secondary antiserum (1:500) was Alexa488 anti-mouse and Alexa594 anti-rabbit IgG with blocking buffer. To determine the nuclear co-labeled cells, each field is 550 × 550 μm in area. Total numbers of NeuN, DCX, GFAP, or IBA-1 cells were counted per section, and co-labeling of Nrf2 or β-catenin with DAPI to indicate nuclear co-labeling cells were counted from five different sections from each of six animals. Regions analyzed were the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone. The nuclear co-labeling with DAPI was confirmed using confocal imaging with 2-μm Z-steps using an FV1000 MPE confocal microscope.
Protein concentration of TNF-α and IL-1β was measured in tissue lysates from hippocampus and cortex using enzyme-linked immunosorbent assay (ELISA) from Raybiotech protein assay. About 100 μl of 100 μg sample concentration was added into appropriate wells and incubated overnight at 4 °C with gentle shaking. The following day, the solution was discarded and the plates were washed four times with 1× wash solution (Raybiotech). Plates were incubated for 1 h at room temperature with detection antibody and washed four times. Of HRP streptavidin solution, 100 μl was added to each well and then incubated for 45 min at room temperature and washed four times. Of TMB (Raybiotech), 100 ul was added to each well and incubated for 30 min at room temperature in the dark. About 50 μl of stop solution (Raybiotech) was added. Absorbance was measured at 450 nm immediately.
Results and discussion
NT-020 attenuates inflammation in the aged hippocampus
The aged hippocampus is a pro-inflammatory environment
Expression of cytokines and chemokines in aged brain
Chemokine ligand 19
Basal leukocyte migration
Chemokine ligand 2
Chemokine ligand 3
Chemokine ligand 4
Natural killer cells/monocytes
Chemokine ligand 5
Chemokine ligand 10
Chemokine ligand 11
Chemokine ligand 1
CD4+ T cells
Tumor necrosis factor
Interleukin 1, alpha
Interleukin 1, beta
Interleukin 1, receptor antagonist
NT-020 increases expression of anti-inflammatory cytokines
Expression of pro-inflammatory cytokines is attenuated by the NT-020 diet
Leukemia inhibitory factor
Glucose phosphate isomerase
Chemokine (C-X3-C motif) ligand 1
Chemokine (C-X-C motif) ligand 12
Interleukin 1 receptor antagonist
Interleukin 1 alpha
Chemokine (C-C motif) ligand 19
Chemokine (C-C motif) ligand 2
NT-020 increases nuclear expression of Nrf2 in the dentate gyrus of the hippocampus
NT-020 increases nuclear localization of β-catenin in the dentate gyrus of aged animals
Wnt ligand binding to its receptor triggers an accumulation of intra-cellular β-catenin that correlates with overall Wnt activity . To gain better insight into the activity level of the Wnt pathway, we stained hippocampus sections as above for Nrf2 for nuclear co-localization with β-catenin. The aged group had reduced percent of DCX positive cells with nuclear co-labeled β-catenin although it only approached significance (Fig. 4). However, compared to control, rats on the NT-020 diet have a higher percent of nuclear co-localization of β-catenin in all cell types. This supports the hypothesis that the NT-020 diet increases overall activity of the Wnt pathway in aged animals. Similar results are observed in the SVZ (Additional file 3: Figure S3). To examine this further, we analyzed gene expression of Wnt target genes.
NT-020 increases expression of Wnt target genes
Wnt target gene expression is altered with age
Expression of Wnt targets is decreased in aged hippocampus
Functional gene group
Glial cell-derived neurotrophic factor
Bone morphogenetic protein 4
Fos-like antigen 1
SRY-box containing gene 9
Secreted frizzled-related protein 2
Transducin-like enhancer of split 1)
NT-020 increases expression of pro-neurogenic genes
NT-020 diet increases expression of genes involved in regulating self-renewal
Functional gene group
Glial cell-derived neurotrophic factor
Delta-like 1 homolog (Drosophila)
Differentiation and development
Inhibitor of DNA binding 2
Differentiation and development
Fibroblast growth factor 4
Secreted frizzled-related protein 2
Transducin-like enhancer of split 1 (E(sp1) homolog, Drosophila)
WNT1-inducible signaling pathway protein 1
Wingless-type MMTV member 3A
The impact of age-dependent inflammation in the CNS is known to drive the progression of neurodegenerative disease and contribute to the decline of tissue homeostasis even in the absence of an underlying disease. The negative impact of inflammatory cytokines on processes vital for cognitive function has been well documented (see review ). While it is not fully understood how declining neurogenesis directly impairs learning, it has been shown to be an early event in the pathology of several diseases including Alzheimer’s . This report describes for the first time an increase in Wnt antagonists in the aged hippocampus and their attenuation by supplementation with NT-020. It is not clear whether this occurs as a direct result of the associated attenuation of inflammation and increase in Nrf2-ARE pathways or by an independent mechanism. However, signaling in the niche rarely occurs unilaterally, and it is likely that these compounds act on supporting cells such as astrocytes or microglia in addition to actions directly on the neural progenitor cells themselves. Another finding that may be of particular importance in the NT-020 treatment group is an increase in anti-inflammatory chemokines CX3CL1 and a decrease in chemokines such as CCL19 and CCL2 that are upregulated during periods of inflammation and facilitate the invasion of peripheral leukocytes . While we did not directly measure leukocyte invasion or blood-brain barrier permeability, it is known to be altered with age  and it would be interesting to examine the effectiveness of NT-020 supplementation on these parameters in disease models involving chronic inflammation.
It is clear that an age-related increase in microglial priming has direct actions on the neurogenic niche. Aged microglia when co-cultured with neural progenitors reduces stem cell proliferation . It has been suggested that this impairment of neurogenic niche function is driven, at least in part, by Nrf2 . Treatments that increase Nrf2 reduced microglial priming and reduced the effect of aged microglia to inhibit neural progenitor proliferation ; interestingly, these authors also suggested that this was associated with increased Wnt signaling , all of which were observed in this study. Our findings demonstrate increased Nrf2 translocation to the nucleus after NT-020 treatment and an increase in HO-1, one of the enzymes regulated by this transcription factor. Nrf-2 has been shown to protect neurons from increased oxidative stress during periods of inflammation . Further, Nrf-2 plays a role in microglial priming as the absence of Nrf2 changes microglial phenotype towards that of increased M1 , the primed microglial phenotype that is observed with normal aging . Recent evidence linking Nrf2-ARE to regulation of immune cells include that Nrf2-ARE is essential for promoting phagocytosis of phosphorylated tau by microglia/macrophages as shown by a reduction in phagocytosis using a Nrf2 decoy . In addition, increased expression of Nrf-2 has been shown to attenuate inflammation by blocking NF-κβ activity .
Taken together, our results demonstrate that NT-020 at concentrations attainable through dietary supplementation effectively target multiple processes that contribute to cognitive decline during aging as well as progression of neurodegenerative disease.
This work was supported by the VA Merit grant 5101BX-000595 and NIH AG044919.
The networks, functional analyses, etc. were generated through the use of QIAGEN’s Ingenuity Pathway Analysis (IPA® QIAGEN Redwood City, www.qiagen.com/ingenuity).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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