1Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat.
2,3University Institute of Pharma Science, Chandigarh University Mohali Punjab .
4,5Indira College of Pharmacy, Tathwade Pune. SPPU (Savitribai Phule Pune University).
6Dr. Shivajirao Kadam College of Pharmacy, Kasabe Digraj, Sangli, Maharashtra, India
Through antioxidant, anti-inflammatory, and neuroprotective actions, vitamin D, a fat-soluble vitamin, and its receptor, VDR, support brain health. VDR alters mechanisms associated with AD pathogenesis, including tau protein hyperphosphorylation and amyloid-beta (A?) metabolism, which are characteristics of the illness. According to this review, VDR activation promotes the clearance of A? and inhibits the enzymes that lead to tau and A? pathology. VDR also affects neuroinflammatory responses by inhibiting pro-inflammatory pathways and increasing anti-inflammatory cytokines. These outcomes demonstrate how VDR preserves cognitive function and synaptic plasticity by lowering oxidative stress, neuroinflammation, and neuronal death. Polymorphisms in the VDR gene have been linked to varying risks of developing AD across populations, suggesting genetic and environmental interactions in disease progression. Clinical and preclinical studies demonstrate that Vitamin D supplementation, through VDR activation, can improve cognitive outcomes, reduce A? deposition, and mitigate neuroinflammation. However, variability in these results necessitates further research to determine optimal dosages and therapeutic strategies. The evidence positions VDR as a promising therapeutic target for AD. Future studies should focus on unraveling the intricate pathways of VDR-related neuroprotection, exploring its genetic implications, and refining Vitamin D-based interventions to maximize therapeutic benefits for neurodegenerative diseases like Alzheimer’s.
Alzheimer's is a progressive, neurodegenerative disease that primarily impairs neurobehavioral skills. It accounts for 60–80% of cases. The buildup of tau protein and ?-amyloid plaque in the brain causes brain cell death and a reduction in cognitive abilities, making it the most prevalent type of dementia. Numerous studies have demonstrated the antioxidant, anti-inflammatory, and neuroprotective qualities of vitamin D. It also plays a critical role in A? neurotoxicity and promotes its enzymatic breakdown and clearance through increased production of the LRP-1 protein. Vitamin-D insufficiency is thought to raise the incidence of AD, and vitamin supplements may assist AD patients experience less neurodegeneration [1]. Being a fat-soluble vitamin, vitamin D is also important for maintaining healthy bones and the immune system. In fact, a lack of this vitamin has been connected to several illnesses, including osteoporosis, diabetes, cardiovascular diseases, sclerosis, dementia, depression, rheumatoid arthritis, allergies, infectious diseases, and some types of cancer. Consequently, the fact that it is linked to numerous illnesses indicates that the VDR is an essential immune modulator. [2-3]. Other immunohistochemical studies show that VDR is present in both human and animal brain structures, including the hypothalamus, hippocampus, amygdala, stria terminalis, throughout the olfactory system, and more abundantly in the hypothalamus, substantial nigra region, and neocortex. The VDR is expressed in different regions of the encephalon and has been found in various neuroglial cells. The hippocampus CA1 and CA2 pyramidal cells have the highest VDR immunoreactivity. [4-8]. One study suggests that there are 1778 ligands which specifically binds to the VDR receptor which have been identified so far and the advancement in understanding their structural and functional relationship enables the modification of structure of 1,25(OH)2D3 and towards low-calcaemic analogues [9]. Hence, there are different Vitamin-D receptor depending upon their pathway to utilize vitamin-D i.e., Genomic, and Non-Genomic pathways. VDR basically function in genomic while Pdia3 work under non-genomic pathways. A comparative study on both the pathway in rat’s transcript the expression of VDR in brain cells was less abundant than that in typical vitamin-D in target organs, whereas Pdia3 had the opposite expression. Among the tested various brain cell phenotypes, the highest expression of VDR was found in astrocytes whereas, Pdia3 was abundantly expressed in neurons, astrocytes, and endothelial cells. Thus, astrocytes were suggested to be the most likely cell type to respond to calcitriol at the genomic level, whereas other cell types could be responsible for its rapid non-genomic effects. While, some studies also demonstrate the role of Vitamin-D in brain ageing and neurodegenerative diseases, such as AD and PD by reducing oxidative stress, promoting pro-survival and anti-inflammatory signalling, and protecting neuronal cells. According to certain research, vitamin-D deficiency may raise the risk of age-related illnesses, while supplements may slow down the aging process of the brain by lowering age-related markers including inflammation and A? buildup. It is still unknown what the ideal serum concentration of vitamin D is to slow down the aging of the brain. According to several research conducted in rat models, vitamin D has a neuroprotective impact that improves learning and memory, reduces oxidative stress, neuroinflammation, and neuronal loss by causing an intrahippocampal A?(1–40) injection [10,11]. However, VDR activation also stimulates anti-inflammatory signalling pathways in the central nervous system and enhances the production of neurotrophins genes. Thus, vitamin D's neuroprotective and anti-inflammatory properties aid in lowering brain inflammation, a defining feature of Alzheimer's disease [12]. The amount of calcitriol in the brain can affect the expression of VDR; research has shown that rat oligodendrocytes and microglia have higher levels of VDR mRNA, although other brain cells, such as astrocytes, did not [13,14]. Thus, as seen in the lupus model, where VDR was unregulated in the hippocampus, inflammation also influences VDR expression [15]. Additionally, following traumatic brain injury, vitamin D was observed to promote anti-inflammatory microglial polarization and reduce neuroinflammation by suppressing the TLR4/MyD88/NF-?B signalling cascade [16]. Therefore, VDR plays pivotal role in maintaining synaptic plasticity and thereby neuronal survival. Like VDR regulate BDNF which is an essential protein for neuronal survival and synaptic plasticity [17]. Further, the activation of VDR show inhibition of production of pro-inflammatory cytokines and ROS, by production of anti-inflammatory cytokines and antioxidant enzymes which suggest VDR protections against neuroinflammation and oxidative stress. Hence, genetic variation of VDR is associated with risk of AD. Also, certain VDR variant may be less sensitive to vitamin-D increasing the risk of AD [18].
Fig.1:- Potential mechanism by which VDR influences various biological processes
Molecular mechanism of VDR in pathology of AD
Vitamin D is a fat-soluble vitamin obtained from dietary sources and synthesized in the skin upon exposure to ultraviolet-B (UVB) radiation. The VDR is widely expressed in the various regions of brain i.e., hippocampus, cortex, cerebellum, and substantia nigra, which are critical for cognition, memory, and motor function, particularly which is vulnerable to AD pathology. Hence, the presence of VDR in these regions suggests that vitamin D plays a pivotal role in maintaining brain health. Additionally, VDR is expressed in glial cells, including astrocytes and microglia, indicating its involvement in neuroinflammatory processes [19,20]. VDR exerts its effects through both genomic and non-genomic mechanisms. Thus, after their activation, vitamin-D binds to VDR, which forms a heterodimer with the retinoid X receptor (RXR) and this complex binds to vitamin-D response elements (VDREs) in the promoter regions of target genes & regulates their transcription [21,22,23]. Vitamin D, traditionally known for its role in calcium homeostasis and bone health, also exerts significant effects on brain function. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], mediates its biological effects through binding to VDR, which is expressed in various tissues, including the brain [24]. The genomic pathway which involves the binding of the VDR-RXR complex to VDREs, leading to the regulation of gene transcription which involves in the A? metabolism, antioxidant effect, and neuroprotection. While, non-genomic pathways actions of VDR are mediated by rapid signalling pathways, such as the activation of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways, which are crucial for cell survival and neuroprotection.[25,26] A? accumulation which is a central event in AD pathology, & leads to the formation of amyloid plaques and disrupt neuronal functions. Hence, several studies demonstrated that VDR activation can modulate A? metabolism by influencing the expression of enzymes involved in A? production and clearance [27]. For instance, VDR activation can leads to the expression of neprilysin and insulin-degrading enzyme (IDE), which are involved in the degradation of A?. Moreover, it also inhibits the expression of ?-secretase (BACE1) which is responsible to produce A? from amyloid precursor protein (APP)[28,29]. Thus, VDR activation has been also shown to reduce tau hyperphosphorylation which leads to the formation of neurofibrillary tangles (NFTs) which is another hallmark of AD via inhibition of glycogen synthase kinase-3? (GSK-3?), a key enzyme involved in tau phosphorylation. Additionally, it also modulates the activity of protein phosphatase 2A (PP2A), which dephosphorylates tau, by further contributing to the reduction of tau pathology in AD [30], [31]. Microglia, the resident of immune cells of the brain, become activated in response to A? accumulation, leading to the release of pro-inflammatory cytokines that exacerbate neuronal damage in response of neuroinflammation which plays a pivotal role in the progression of AD [32,33] . Hence, VDR activation has been shown to exert anti-inflammatory effects by downregulating the expression of pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-?) and interleukin-6 (IL-6), and by promoting the expression of anti-inflammatory cytokines like interleukin-10 (IL-10). Furthermore, VDR inhibits the activation of nuclear factor-kappa B (NF-?B), a key transcription factor involved in the inflammatory response, thereby reducing neuroinflammation in AD [34]. The signalling of VDR also promotes neuroprotection through various mechanisms, including the enhancement of antioxidant defence, via modulation of calcium homeostasis, and the inhibition of apoptosis. And upon VDR activation upregulates the expression of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), which protects neurons from oxidative stress. Additionally, VDR also regulates the expression of calcium-binding proteins, such as calbindin, which helps in maintaining calcium homeostasis and prevent excitotoxicity. Thus, it also inhibits the expression of pro-apoptotic factors, such as Bax, and promotes the expression of anti-apoptotic factors, such as Bcl-2, thereby preventing neuronal apoptosis in AD.[35,36] Various recent studies have significantly advanced the understanding of the role of the Vitamin D Receptor (VDR) in amyloid-beta (A?) metabolism, particularly in the context of Alzheimer's disease (AD). Recently in 2023, a review highlighted the VDR's involvement in neuroprotective mechanisms, particularly its role in mitigating oxidative stress, neuroinflammation, and amyloid plaque formation in Alzheimer's disease. Hence, this study discusses how VDR gene polymorphisms can influences the pathways and potentially contribute to the progression of AD. Thus, there activation appears to regulate several neuroprotective genes, which might reduce A? accumulation and enhance its clearance from the brain [37]. Another recent study explored the localization of VDR on the neuronal plasma membrane, specifically its co-localization with proteins involved in APP processing, such as ADAM10 and Nicastrin. Hence, this finding is crucial as it suggests a direct role for VDR in the modulation of A? production and clearance. The study also highlighted the potential co-localization of VDR with APP, indicating a more intricate involvement in amyloid metabolism than previously understood [38,39]. As proven multi-faceted role of VDR in neurodegenerative diseases, there is growing interest in targeting this receptor for therapeutic interventions. Thus, various narrative reviews from early 2023 emphasizes VDR's potential as a target for treating not only Alzheimer's but also other neurodegenerative disorders like Parkinson's disease. Hence, there activation could counteract the neurodegenerative processes by reducing inflammation and promoting neuron survival [40,41]. These findings collectively suggest that VDR is a critical player in A? metabolism and could be a promising target for new therapeutic strategies in Alzheimer's disease. Further research, particularly clinical trials, is needed to validate these findings and develop effective VDR-based therapies.
Fig.2:- Latest Clinical Evidence on Vitamin D Receptors role in Alzheimer Disease Pathology
VDR Polymorphism & Risk in AD
As per the researches the involvement of VDR in regulating neuroinflammation, oxidative stress, and A?-clearance, polymorphisms in the VDR gene could theoretically alter the risk of developing AD by modulating these pathways.[48] Several single nucleotide polymorphisms (SNPs) in the VDR gene have been identified, with some linked to various diseases, including osteoporosis, cancer, and autoimmune disorders [49]. Several studies have investigated the association between VDR polymorphisms and AD risk, yielding mixed results. Some key findings are summarized below:
FOKI: There remains controversy regarding the interaction of FokI with AD and some studies have positive association. Other studies found that the risk of AD was reduced among FOKI TT genotype individuals because of the shorter lengths of the VDR protein and thus enhanced activity of VDR and better neuroprotective effects. Other researchers have found no relevance at all between the FokI polymorphism and the risk of becoming AD indicating that there may be moderating factors such as Vitamin D levels and or inter-gene interactions to be significant..[50,51]
BSMI: The BSMI polymorphism has been associated with AD risk in some populations, with individuals carrying the B allele showing a higher risk of developing the disease. This may be due to altered VDR mRNA stability and reduced receptor expression, leading to diminished neuroprotective effects of Vitamin D.[52,53]
APAI: Like BSMI, APAI has also been associated with AD risk in some studies. The A allele has been linked to an increased susceptibility to AD in certain populations, potentially through its influence on VDR gene regulation. [54]
TAQI: Attention was paid to the TAQI polymorphism, which has shown variable association with AD risk. Some studies ascertained higher risk to AD with the T allele but others found no association. The effect of TAQI on VDR function is less straightforward, since it does not alter the amino acid sequence of the protein.[55,56] The mechanisms by which VDR polymorphisms influence AD risk are not fully understood, but several hypotheses have been proposed:
It is important to note that the associations between VDR polymorphisms and AD risk may vary across different populations. For example, some studies have found significant associations in European populations but not in Asian or African populations. This variability may be due to differences in genetic background, environmental factors (such as sun exposure and dietary Vitamin D intake), and the presence of other AD risk genes (such as ApoE ?4). Additionally, interactions between VDR polymorphisms and other genes involved in Vitamin D metabolism, such as CYP27B1 (which converts Vitamin D to its active form) and CYP24A1 (which degrades active Vitamin D), may also influence AD risk. [62, 63]
Clinical Evidences Linking Vitamin-D & Alzheimer Disease
Vitamin D-The active form of Vitamin D can be synthesized and received by the encephalon and it is known to modulate neurotransmission, synaptic plasticity, & neuroprotection. The link has been elucidated by compelling studies conducted in laboratory & living organisms in terms of disease development with VIT-D & tho progress with AD. Since amyloid plaques and neurofibrillary tangles characteristic of AD have been shown to be cleared in the body by phagocytic immune cells, this has been investigated and shown that 1,25 (OH)2D can assist the body's innate immune cells able to clear amyloid plaques). For example, macrophages derived from MCI and AD patients exhibit enhanced ability to remove amyloid plaques following treatment with 1,25(OH)2D, and a diet enriched with Vitamin D can reduce the quantity of plaques in A?PP-PS1 transgenic mice, which serve as an AD animal model [64]. The metabolism of APP includes interaction with certain transcription factors like SMAD and transforming growth factor-beta (TGF-?) that interact with VDR/ligand complex in the nucleus and it is important to note that Vitamin D plays a role in decreasing inflammation and oxidative stress in the cerebral microenvironment, which are considered potential mechanisms contributing to neurodegeneration and the pathogenesis of Alzheimer's disease (AD). Inadequate levels of vitamin D (25–49.9 ng/ml) as well as deficient levels (<25>
Therapeutic Potential of VDR Activation in Alzheimer’s Disease
As per the recent emerging trend various researches has spotlighted Vitamin D and Vitamin D Receptor (VDR), as potential therapeutic targets in AD [72]. VDRs are nuclear receptors that mediate the effects of Vitamin D on gene expression, influencing various biological processes such as immune response, neuroprotection, and cellular homeostasis [73]. While preclinical studies provide compelling evidences for the neuroprotective effects of Vitamin D in Alzheimer disease with more variable clinical data. Some trials have reported improvements in cognitive function with Vitamin D supplementation, while others have found no significant effects [74]. These discrepancies may be due to differences in study design, dosage, baseline Vitamin D levels, and the duration of supplementation. Nonetheless, Vitamin D remains a promising candidate for AD therapy, particularly as part of a multi-targeted approach that includes lifestyle modifications and other pharmacological interventions [75]. The therapeutic effects of Vitamin D in Alzheimer’s Disease (AD) are mediated through several key mechanisms. These mechanisms include anti-inflammatory effects, amyloid-beta clearance, calcium regulation, and cognitive enhancement. Each of these mechanisms plays a crucial role in modulating AD pathology and improving disease outcomes. Therefore, the therapeutic effects of Vitamin D in Alzheimer's Disease are multifaceted, involving anti-inflammatory actions, enhancement of amyloid-beta clearance, stabilization of calcium levels, and improvement of cognitive function. These mechanisms work together to address various aspects of AD pathology, offering a promising approach for the treatment and management of the disease. Further research is needed to fully understand these mechanisms and to optimize Vitamin D-based therapies for AD. Hence, various potential mechanism of actions are as follows:
Neuroinflammation is a significant contributor to AD pathology, characterized by the activation of microglia & the production of pro-inflammatory cytokines. Vitamin D and VDR have been shown to exert anti-inflammatory effects in the brain, which can helps in mitigating neuroinflammation in AD[76],[77]. Thus, Modulation of cytokines leads to VDR activation which reduces & inhibits the levels of pro-inflammatory cytokines such as TNF-? and IL-1?, along with that the activation of VDR also affects microglial activation which plays crucial role in neuroinflammatory processes. Hence, Vitamin D helps in decreasing the inflammatory response in the brain & also inhibits the activation of microglial cells , therefore reduces the neuronal damage by inhibiting the release of neurotoxic substances that exacerbate AD pathology [78,79,80].
Amyloid-beta (A?) plaques are a hallmark of AD, and their accumulation is linked to neuronal toxicity with cognitive decline. Vitamin D has been implicated in modulating both the production and clearance of A?, which is critical for managing AD pathology [81],[82]. Along with Vitamin D also facilitates the clearance of A? from the brain by influencing the function of the brain’s clearance mechanisms. Thus, VDR activation promotes the activity of enzymes and pathways involved in the breakdown and removal of A?. This process helps to reduce the accumulation of amyloid plaques and the associated neurotoxicity. Hence, Vitamin D also affects the production of A? by modulating the processing of APP by inhibiting the cleavage of APP by ?-secretase, which reduces the generation of A? peptides. This reduction in A? production contributes to decreased plaque formation and mitigates its harmful effects on neurons[83, 84].
Intracellular calcium levels play a critical role in neuronal health, and dysregulation of calcium homeostasis is associated with AD pathology. Vitamin D regulates calcium levels in neurons, thereby influencing neuronal excitability and survival[85],[86]. Thus, it also helps in maintain intracellular calcium levels by modulating calcium channels and transporters. Hence, proper calcium regulation prevents excitotoxicity, a condition where excessive calcium influx leads to neuronal damage and death. By stabilizing calcium levels, Vitamin D protects neurons from calcium-induced toxicity and supports overall brain health[87]. While excitotoxicity often driven by excessive activation of glutamate receptors, which is a key contributor to neuronal loss in AD. Along with Vitamin D also effect on calcium regulation which helps to prevent excitotoxicity by moderating glutamate signaling and ensuring that calcium levels remain within a safe range, thereby preserving neuronal function and preventing neurodegeneration[88, 89].
Vitamin D has been shown to have a positive impact on cognitive function through several mechanisms, including effects on synaptic plasticity and neurogenesis[90], [91]. Synaptic plasticity, the ability of synapses to strengthen or weaken over time, is essential for learning and memory. Vitamin D promotes synaptic plasticity by enhancing the expression of BDNF and other neurotrophins that support synaptic health. Improved synaptic plasticity contributes to better cognitive function and memory retention [92,93]. Neurogenesis, the process of generating new neurons, is crucial for cognitive function and brain repair. Vitamin D has been shown to stimulate neurogenesis in the hippocampus, a brain region critical for memory formation. By promoting the growth of new neurons and supporting existing neuronal networks, Vitamin D enhances cognitive abilities and potentially slows cognitive decline in AD[94,95].
Fig.3:- Therapeutic Potential of Vitamin D Receptors (VDRs) in Alzheimer’s Disease (AD) as per the recent research studies which underscores the therapeutic promises approach of Vitamin D Receptors (VDRs) in Alzheimer's Disease (AD). In 2023, studies on AD transgenic mice revealed that Vitamin D3 supplementation reduced amyloid-beta deposition and improved cognitive function by inhibiting amyloid precursor protein (APP) processing via VDR. High-dose Vitamin D treatment in early-stage AD patients (2022) slowed cognitive decline through VDR-mediated modulation of neuroinflammatory pathways. Chen et al. (2021) showed that VDR agonists decreased tau phosphorylation and aggregation in human neuronal cells by downregulating GSK-3? activity. Another 2021 study found that combining Vitamin D with NSAIDs enhanced neuroprotection and reduced neuroinflammation in AD mice through a synergistic effect on VDR activation and COX inhibition. Additionally, a 2020 genetic study identified VDR polymorphisms linked to AD risk, suggesting that genetic variants influence neuroprotective gene expression.
CONCLUSION
Alzheimer is an irreversible progressive neurodegenerative disease accounts for 60-80?ses affecting neurobehavioral functions & characterized by accumulation of A? & Tau proteins leading to death of neuronal cells. Vitamin-D which is the fat-soluble vitamin plays a vital role in brain ageing. A?-neurotoxicity, & neurodegenerative diseases via its Antioxidant, Anti-inflammatory & Neuroprotective effects by enhancing expression of LRP-1 protein etc. Thus, VDR play a key role as immune-modulator through either genomic pathways or non-genomic pathways. Therefore, VDR activation also inhibits the expression of BACE1 & GSK-3? which is responsible to produce A? from APP and Tau hyperphosphorylation which are the hallmarks of AD. Hence, VDR genetic polymorphisms associated with higher AD risk in certain populations. As per the recent research evidences Vitamin-D also known as neurosteroid which is known to support neurotransmission, synaptic plasticity, and neuroprotection while its insufficiency is linked to the development of chronic neurodeteriorating brain conditions. Vitamin-D or VDR can proves as the promising potential therapeutic target due to its crucial multifaceted role in AD pathology but the further research investigations are required to fully understand these interlinking between mechanisms, potential therapeutic targets, & novel delivering strategies to optimize Vitamin D-based therapies for neurodeteriorating diseases like Alzheimer.
REFERENCES
Arun Pachauri, Kailash Singh Bisht, Anupama Sinha, Lokesh Paranjape, Omkar Sutar, Vrushali Murari*, The Role of Vitamin-D Receptor in Alzheimer’s Disease: A Molecular and Clinical Perspective, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 2087-2104. https://doi.org/10.5281/zenodo.14472964