Vitamin D deficiency as a potential risk factor for accelerated aging, impaired hippocampal neurogenesis and cognitive decline: a role for Wnt/β-catenin signaling

Introduction

Vitamin D is an essential fat-soluble vitamin that consists of two equally inactive forms, vitamin D₂, also called ergocalciferol and vitamin D₃ or cholecalciferol. Vitamin D2 can be obtained from vegetable dietary sources and food supplements, whereas vitamin D3 not only can be obtained from dietary sources, but it can also be produced by the human skin after exposure to ultraviolet B radiation in sunlight, with cutaneous production being the main source in the general population. As illustrated in Figure 1, either vitamin D₂ or D₃ must also be activated by transformations in the liver and kidney. Many variables influence the amount of ultraviolet B radiation from sunlight that reaches the skin and its effectiveness at facilitating the synthesis of vitamin D₃. These variables include time of day, season, latitude, altitude, clothing, sunscreen use, pigmentation, and age. The activation of these vitamins into active metabolites occurs in two stages: the first stage is the hydroxylation of carbon 25 of vitamin D₂ or D₃ catalyzed by 25-hydroxylase leading to calcidiol (also called 25(OH)D or 25-hydroxyvitamin D) in the liver. The second stage is the transformation of 25(OH)D onto calcitriol (also called 1,25(OH)₂D₃ or 1,25-dihydroxyvitamin D), the most active form of vitamin D, catalyzed by 1α-hydroxylase mainly in the kidney. Although, classical function of vitamin D was always limited to calcium and phosphorus homeostasis, the discovery of vitamin D receptor (VDR), present in most tissues and cells in the body, including the brain [1, 2], meant an increase in the number of studies focusing on vitamin D functions. VDR can regulate a large number of genes through 1,25(OH)₂D₃. The binding of 1,25(OH)₂D₃ to VDR generates a cytosolic complex that regulates gene transcription and many biological functions (Figure 1). VDR/1,25(OH)2D₃ complex can interact with retinoid X receptor (RXR) in the cytosol to form a heterodimeric complex which is recruited to the VDRE (Vitamin D Receptor Element) placed in the promoters of target genes to activate its regulation [3] (Figure 1). The best well known function of 1,25(OH)₂D₃ is the regulation of calcium homeostasis and bone mineralization. However, ontology analysis describe 11,031 putative VDR target genes identified, 43% of which were involved with metabolism, 19% with cell and tissue morphology, 10% with cell junction and adhesion, 10% with differentiation and development, 9% with angiogenesis, and 5% with epithelial to mesenchymal transition [4]. The number, the location and the VDR expression regulation are determined by cell type [5–7]. These genes are involved in several processes such as cell proliferation, cancer, immune response, glucose homeostasis, cardiovascular homeostasis and activity of the nervous system [8–11].

Figure 1. Metabolism of vitamin D. Vitamin D3 is synthesized in the skin from provitamin D3 (7-dehydrocholesterol) under the influence of UV light. Vitamin D2 (ergocalciferol) is obtained from vegetable dietary sources where it derives from the plant sterol ergosterol. Vitamin D is metabolized first to calcidiol (25(OH)D), and later to the active form calcitriol (1,25(OH)₂D₃). Interaction of 1,25(OH)₂D₃ with the vitamin D receptor (VDR), which is an intracellular transcription factor, facilitates its binding to DNA sequences. The binding of the complex VDR/1,25(OH)₂D₃ to these regulatory sequences (vitamin D response elements (VDREs)) regulate transcription of genes involved in many different cellular homeostatic functions.

In the human brain, VDR and vitamin D-metabolizing enzymes are expressed by cerebral structures such as prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra [12, 13]. In neurons, vitamin D plays different key roles participating in the suppression of oxidative stress, inhibition of inflammation, neuroprotection, down-regulating inflammatory mediators and up-regulating many neurotrophins [13, 14]. Proteomics and gene array analyses show that low levels of vitamin D during gestation influence the regulation of genes involved in nervous system development. These genes play significant roles in the cytoskeletal maintenance, mitochondrial function, synaptic plasticity and cellular proliferation and growth [15]. Regarding neurotrophins, vitamin D exerts neurotrophic support participating in the synthesis of neurotrophic factors. It participates in the synthesis of nerve growth factor (NGF) upregulates, the synthesis of glial cell line-derived neurotrophic factor (GDNF) and neurotrophin 3 (NT-3), and also downregulates levels of neurotrophin 4 (NT-4) [9, 16, 17].

Although there are probably around 50 known metabolites of vitamin D, measurement of serum 25(OH)D is clinically used to define the vitamin D status. The threshold to define adequate stores of 25(OH)D in humans has not been clearly established. Diversity of opinions among researchers has generated different thresholds of vitamin D for human health. Thus, the Institute of Medicine has stablished the optimal concentration of 25(OH)D serum level being 50 nM (20 ng/mL) for skeletal health [18], insufficiency between 30–50 nM, and deficiency below 30 nM (12 ng/ml), whereas the International Osteoporosis Foundation considers that the adequate values of 25(OH)D for skeletal health are higher than 75 nM (30 ng/mL) [19]. Despite the lack of consensus, it is clear that low levels of vitamin D have detrimental consequences for human health [20].

Though the main source of vitamin D is the sunlight, its deficiency has a high prevalence worldwide and affects half of the world population without excluding those in countries with sun exposure over all the year [21, 22] thus leading to a great variety of health problems. In addition to the widely studied actions of 1,25(OH)₂D₃ on intestinal calcium absorption and bone physiology, studies in animal models show that 1,25(OH)₂D₃ exerts tumor-suppressive actions (anti-angiogenic, anti-invasive, antimetastatic) [23] in several cancers and epidemiological studies report that vitamin D exerts protective effects against several neoplasia, particularly colorectal cancer [24]. Vitamin D deficiency is associated as well with several brain diseases such as schizophrenia, autism spectrum disorders, multiple sclerosis, dementia and Alzheimer’s disease [25–33].

Neurogenesis and Wnt signaling

Wnt signaling pathways in the central nervous system

Typically, Wnt proteins play essential roles in different signaling pathways in cellular proliferation, differentiation and cell migration during central nervous system development but recently, studies have shown that Wnt signaling is not only implicated in embryonic development but also in the adult state. Wnt ligands are constitutively expressed in the adult brain and have a role at least in the maintenance of adult brain neurogenesis [82, 83]. The active role of Wnt during brain development is regulating neurogenesis and synaptogenesis of the neural tube [84]. Therefore, constitutive expression of Wnt ligands in the hippocampus of the adult brain might suggest an important role for Wnt in the maintenance and protection of adult hippocampal neurogenesis during adulthood. Moreover, it has been suggested that its deregulation is crucial in neurogenesis during aging [85] and in several neurological disorders such as Alzheimer’s disease, Parkinson’s disease or Schizophrenia [86]

The importance of Wnt signaling can be inferred from the conservation of this pathway in the different organisms across evolution including humans. There are three Wnt stimulated pathways very well characterized: the canonical β-catenin dependent Wnt pathway, the noncanonical β-catenin independent pathways: planar cell polarity pathway (PCP) and calcium pathway (CaP). These pathways are activated by the binding of a Wnt ligand (Wnt 1-19) to a Frizzled (Fzd) receptor and the LDL-Receptor-related protein coreceptor (LRP5/6) resulting in the activation of Disheveled (DVL) protein which initiate different signaling cascades [87–89].

In the Wnt canonical pathway, Fzd and DVL activation avoid the degradation of β-catenin (Figure 2). In the absence of Wnt, β-catenin is continuously degraded by a protein complex composed of the scaffold proteins Axin and adenomatous polyposis coli (APC), and the kinases casein kinase 1 (CK1) and glycogen synthase kinase 3 beta (GSK3β). CK1 and GSK3β sequentially phosphorylate β-catenin, resulting in β-catenin being recognized and ubiquitinated by the β-Trcp ubiquitin ligase, followed by proteasomal degradation. Binding of Wnt to a Fzd receptor complex induces the binding of Dvl to Fzd and the recruitment of Axin to the membrane, which impairs the destruction complex through the inactivation of GSK3β, promotes the release of β-catenin, and its accumulation in cytoplasm and nuclei leading to β-catenin-activated gene expression [90–92]. Inhibitors of this pathway are the Dickkopf proteins 1-4 (DKK 1-4) and the secreted frizzled related proteins 1-5 (SFRP 1-5) [88]. This branch of the Wnt signaling pathway plays key roles in regulating cell fate, proliferation and survival [93]. The noncanonical pathways PCP and CaP are activated by Wnt4, Wnt5a and Wnt11. These pathways control gene expression through different mechanisms involving RhoA/Rock kinases or the calmodulin kinase CamKII respectively [94]. This branch is more associated with differentiation, cell polarity and migration [93]

Figure 2. Activation of the Wnt canonical pathway induces β-catenin-regulated gene expression. Left panel: binding of Wnt to a Frizzled receptor (Fzd) allows its association to Dishevelled proteins (DVL) sequestering Axin and avoiding the formation of the complex composed of Axin, the adenomatous polyposis coli (APC), the kinases casein kinase 1 (CK1) and glycogen synthase kinase 3 beta (GSK3β), which phosphorylates β-catenin, resulting in β-catenin being ubiquitinated by the β-Trcp ubiquitin ligase, followed by proteasomal degradation. Right panel: in the absence of Wnt β-catenin is degraded, whereas Wnt-mediated activation of Fzd induces expression of genes regulated by β-catenin [92].

Wnt and adult neurogenesis

In multiple mammalian tissues canonical Wnt signals within the niche act as self-renewal short range signals for stem cells tissues [89]. There is also increased evidence about Wnt involvement in adult neurogenesis. It has been demonstrated that adult hippocampal progenitor cells express different Wnt ligands which can regulate adult hippocampal neurogenesis acting on both canonical and non-canonical signaling pathways. Recent studies indicate that two major branches of the Wnt signaling pathway, the Wnt/β-Catenin and Wnt/PCP pathways, play essential roles in various steps of adult neurogenesis [86]. However, at least 19 Wnt proteins and 10 Fzd receptors have been found [95]. This diversity of signals and receptors complicate the comprehension of the impact of their different roles in mammals.

The overexpression of Wnt ligands that activate the canonical Wnt β-catenin pathway such as Wnt3 increases neurogenesis of adult hippocampal progenitor cells in vitro and in vivo, suggesting that Wnt signaling enhances proliferation of neural stem cells derived from adult CNS [96, 97]. In agreement with this, Wnt3 signaling inhibition blocks neurogenesis in the DG and decreases long-term retention of episodic memory in adult rats [98]. Accordingly, the deletion of Wnt7a reduced drastically the numbers of newborn neurons in the DG of adult mouse brains preventing NPC proliferation and differentiation through the canonical Wnt/β-catenin pathway [99]. In addition, the implication of Wnt pathway is not only revealed by Wnt ligands but also by their Fzd receptors. Fzd1 knockdown reduces the generation of newborn neurons in the DG and changes the migration of neurons [100]. Another Wnt canonical signaling regulator that participates in adult neurogenesis is GSK3β. Overexpression of this kinase inhibits neurogenesis in the adult DG whereas its inhibition facilitates NSC proliferation and neuronal differentiation (reviewed in Marchetti et al. 2020 [86]). Finally, Wnt-signaling must be finely tuned via Wnt-antagonists such as some Dikkopf (DKK) proteins. Dkk1 is a potent inhibitor of SVZ- and SGZ-neurogenesis [83].

An additional role for non-canonical Wnt signaling pathway has also been reported. Wnt5a knockdown in the mouse DG impaired neuronal differentiation of progenitor cells and reduced dendritic development of adult-born neurons. In cultured adult hippocampal progenitors, knockdown of noncanonical Wnt5a reduced neuronal differentiation and morphological development of adult neurons, whereas treatment with Wnt5a had the opposite effect. Arredondo et al. determined that Wnt5a signals through CaMKII induce neurogenesis and promotes dendritic development of newborn neurons through activating Wnt/JNK and Wnt/CaMKII signaling suggesting that Wnt5a act as a niche factor in the adult hippocampus that promotes neuronal differentiation and development [101].

Altogether these evidences support the relevance of Wnt signaling pathway on adult neurogenesis. However, the understanding of the complex regulation of Wnt signaling in neurogenesis in the adult brain remains unclear.

Wnt and the aged brain

It has been proposed that neurogenesis could be finely regulated by the expression of specific Wnt receptors in different cell types in young adults and this regulation is altered in the aged brain [102]. In the young adult, hippocampal astrocytes express Wnt3, which stimulates the canonical β-catenin pathway in neuroblasts promoting proliferation and differentiation via paracrine signaling [97]. Autocrine Wnt signals in NSC and NPC within the DG maintain their proliferative activity [103, 104] via the β-catenin pathway. Furthermore, mature granule neurons in the DG express the Wnt inhibitor sFRP3. The expression of this inhibitor can be greatly reduced depending on neuronal activity leading to proliferation of NPC and maturation of newly generate neurons [105]. Non canonical PCP Wnt signaling also plays an important role in neurogenesis in the young adult by inducing neuroblast differentiation and migration [106]. Wnt activity is different in the aged DG compared to the young adult. A reduction in canonical Wnt activity has been described in the hippocampus of aged animals. Wnt3 expression of hippocampal astrocytes and the number of Wnt3-secreting astrocytes is reduced during aging [107]. Decreased Wnt levels together with an elevated expression of Wnt antagonists, such as DKK1, could partially explain the decline in neurogenesis found in aged adults [107–109]. Loss of the Wnt antagonist DKK1 in aged KO mice results in a restoration of the decline in neurogenesis found in non-mutant aged mice. [109]

An attenuation of Wnt signaling has also been found in the SVZ. Zhu et al. detected decreased canonical Wnt activity in the SVZ of old mice compared to younger mice that could be responsible for the reduced adult neurogenesis in rodents [110]. A negative regulator of Wnt is the p38 mitogen-activated kinase (p38 MAPK), which inactivates GSK3β leading to the attenuation of Wnt signaling. Kase et al. have identified p38 MAPK as a key factor in the proliferation of NPC in adult neurogenic niches. p38 expression in adult NSC/NPC is downregulated during aging. Deletion of p38α in NSC/NPC specifically reduces the proliferation of NPC but not stem cells. Overexpression of p38α in NSC/NPC in the aged mouse SVZ restores NPC proliferation and neurogenesis and prevents age-dependent SVZ atrophy [111].

An effect of Wnt on the transition from qNSC to aNSC that is altered in the aged brain has also been proposed. However, this subject is still an open question. Some evidences point out at a role for canonical Wnt signaling in promoting activation of NSC in the SVZ and DG. Wnt signals produced by astrocytes and NSC induce proliferation and self-renewal of NSC in both niches [97, 99]. Also, elimination of sfrp3 expressed in hippocampal granule neurons results in aberrant NSC activation. Accordingly, sfrp3 gradients regulate qNSC activation regionally. A similar effect is observed upon elimination of DKK1, a Wnt inhibitor expressed by NPC within the hippocampus [105, 109, 112]. In addition, some studies suggest that non-canonical Wnt signaling maintains quiescence of SVZ NSC by facilitating anchoring of NSC within the niche in a mechanism mediated by Rho GTPase Cdc42 [113]. All these suggests that activation requires a switch from non-canonical to canonical Wnt signaling [78]. Wnt signaling molecules have been found to be altered in the pathogenesis of aging. In fact, p38-MAPK is necessary for suppressing the expression of sfrp3 and other Wnt antagonists like DKK1, which inhibit the proliferation of NPCs, and therefore, an age-related reduction in p38 leads to decreased adult neurogenesis via downregulation of Wnt signaling [111].

Studies using mathematical models show that in mice in which the Wnt antagonist DKK1 has been deleted, NSC spend longer periods of time in quiescence but they are more likely to be activated than depleted via their differentiation towards astroglial cells [114]. The study concludes that, high NSC-Wnt activity leads to longer time in quiescence while enhancing the probability of activation.

The activation of VDR depends on the presence of 1,25(OH)₂D₃ which triggers the direct regulation of genes with VDRE (as illustrated in Figure 3). But in some cases, 1,25(OH)₂D₃ can also indirectly regulate genes that do not contain VDRE in their promoters because 1,25(OH)₂D₃/VDR can also regulate other pathways through β-catenin which is required for gene expression in response to Wnt signaling (Figure 3). The relationship of this crosstalk is complex and not fully understood in all tissues and cells. The crosstalk between 1,25(OH)₂D₃ and Wnt/β-catenin pathway has been reported in cancer cells, for example in vitro functional validation studies on melanoma and colon cancer cells showed that elevated 1,25(OH)₂D₃/VDR signaling inhibit Wnt/β-catenin signaling genes [24, 115, 116]. Besides, interactions between vitamin D and Wnt/β-catenin pathway has also been reported in different cellular contexts such as colon cancer cells [117], in which 1,25(OH)₂D₃ acts upregulating the extracellular Wnt inhibitor DKK1 antagonizing of Wnt/β-catenin pathway [118], promoting VDR/β-catenin interactions [119], thus reducing the β-catenin-dependent gene expression or facilitating the sequestration of β-catenin by E-cadherin at plasma membrane adherents junction [117, 119, 120]. Similar mechanisms have been described in other cell types [121, 122].

Figure 3. Vitamin D interferes with β-catenin induced gene expression via different pathways in different cell types. Left panel: in cancer cells vitamin D impairs the Wnt/β-catenin signaling pathway. One of these mechanisms relays on the association of the complex VDR/1,25(OH)₂D₃ to β-catenin to induce VDR-regulated gene expression avoiding β-catenin dependent gene expression. Right panel: in some other non-cancer cell types vitamin D exerts an activating effect of the Wnt signaling pathway by upregulating the expression of the Fzd co-activator Lrp5 or by repressing the expression of the Wnt inhibitors DKK1 y Sfrp2 [116, 171].

The 1,25(OH)₂D₃-induced repression of β-catenin is not the only mechanism of action of 1,25(OH)₂D₃ in the Wnt signaling pathway (Figure 3, left). Interestingly, an upregulation of the Wnt/β-catenin pathway by VDR has been described in osteoblasts and keratinocytes in which 1,25(OH)₂D₃ effects are similar to those of Wnt: 1,25(OH)₂D₃ induces the expression of the Wnt coreceptor Lrp5 in mouse osteoblast [123] while represses Wnt inhibitors Dkk-1 and Sfrp2 in mesenchymal stem cells (Figure 3, right). In skin, deficiency of VDR produces hair loss and a gradual decrease in epidermal stem cells, while the transcriptional effects of β-catenin are impaired thus normal postnatal hair cycling is only possible with combined action of these two pathways [124]. VDR acts as a Wnt effector and β-catenin as a co-activator to induce transcription of genes involved in the hair follicle differentiation [125]. Theses evidences show that Wnt/β-catenin and 1,25(OH)₂D₃ can work together or are linked to regulate their target genes. The mechanism of action diverges depending on the biological system. While vitamin D can act as an antagonist of the Wnt/β-catenin pathway in some cancer cells, it can also act as co-activator of Wnt/β-catenin pathway in other physiological cell types.

Considering the cross talk between vitamin D and Wnt pathway and the considerable number of reports demonstrating a role for Wnt signaling in the regulation of neurogenesis, it would be reasonable to hypothesize that vitamin D may play a role in adult neurogenesis affecting brain tasks associated with neurogenesis such as cognitive performance.

Conclusions

In conclusion, vitamin D has been shown to exert an important role in neurogenesis and neuronal survival. In hippocampal progenitor cells, vitamin D may potentially act as a co-activator of Wnt/β-catenin pathway to preserve neurogenesis in the aged brain. Thus, the decrease of vitamin D during the senescence processes could have a role in the upregulation of Wnt antagonistic signals responsible of the decrease in neurogenesis that may precede the decline in cognitive performance (summarized in Figure 4), and more studies are required to fully understand the relationship between vitamin D, neurogenesis and cognitive performance in the elderly.

Figure 4. Hypothetical role of vitamin D in facilitating the activation of quiescent neural stem cells (qNSC) in the aged brain and its consequences in cognitive impairment. The effects of vitamin D on cognitive decline might be mediated by its capacity to stimulate neurogenesis in the old neurogenic niche. Several factors such as inflammation, and Wnt signaling inhibition facilitate the state of quiescence in NSC diminishing the neurogenic rate [78, 80]. High NSC-Wnt activity leads to longer time in quiescence while enhancing the probability of activation [114]. Vitamin D may activate canonical Wnt signaling through the repression of Wnt inhibitors such as DKK1 and prolonging the time NSC spend in quiescence, increasing their probability to be activated and avoiding being depleted via their differentiation towards astroglial cells [114]. It may be possible that a deficiency in vitamin D results in Wnt signaling imbalance, impairing the gradual activation of NSC required to maintain a neurogenic rate. Thus, hypovitaminosis D might impair these mechanisms leading to a reduction in neurogenesis resulting in cognitive decline.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Funding

This work was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (grant number RTI2018-099908-B-C21), and co-financed by the 2014-2020 ERDF Operational Programme and by the Department of Economy, Knowledge, Business and University of the Regional Government of Andalusia. Project reference: FEDER-UCA18-10664.

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