Vitamin D Signaling Pathway in Neurodegeneration describes a key molecular or cellular mechanism implicated in neurodegenerative disease. This page provides a detailed overview of the pathway components, signaling cascades, and their relevance to conditions such as Alzheimer's disease, Parkinson's disease, and related disorders.
Vitamin D, traditionally recognized for its critical role in calcium homeostasis and bone metabolism, has emerged as a crucial neuroactive hormone with profound implications for neurodegenerative disease pathogenesis. The vitamin D endocrine system operates through a sophisticated signaling network involving the vitamin D receptor (VDR), which is expressed throughout the [central nervous system](/brain-regions/central-nervous-system), and multiple metabolic enzymes that allow local synthesis and activation of vitamin D metabolites within the [brain](/brain-regions/overview). This comprehensive signaling pathway influences [neuron](/cell-types/neurons) survival, synaptic plasticity, [neuroinflammation](/mechanisms/neuroinflammation), and [oxidative stress](/mechanisms/oxidative-stress) responses—all critical processes in neurodegenerative disorders including [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), multiple sclerosis (MS), and [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis).
Vitamin D Signaling Pathway in Neurodegeneration describes a key molecular or cellular mechanism implicated in neurodegenerative disease. This page provides a detailed overview of the pathway components, signaling cascades, and their relevance to conditions such as Alzheimer's disease, Parkinson's disease, and related disorders.
Vitamin D, traditionally recognized for its critical role in calcium homeostasis and bone metabolism, has emerged as a crucial neuroactive hormone with profound implications for neurodegenerative disease pathogenesis. The vitamin D endocrine system operates through a sophisticated signaling network involving the vitamin D receptor (VDR), which is expressed throughout the [central nervous system](/brain-regions/central-nervous-system), and multiple metabolic enzymes that allow local synthesis and activation of vitamin D metabolites within the [brain](/brain-regions/overview). This comprehensive signaling pathway influences [neuron](/cell-types/neurons) survival, synaptic plasticity, [neuroinflammation](/mechanisms/neuroinflammation), and [oxidative stress](/mechanisms/oxidative-stress) responses—all critical processes in neurodegenerative disorders including [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), multiple sclerosis (MS), and [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis).
The biological activity of vitamin D in the [brain](/brain-regions/overview) depends on a complex metabolic cascade that transforms inert precursors into the active hormonal form 1,25-dihydroxyvitamin D3 (calcitriol). Vitamin D3 (cholecalciferol) is either obtained through dietary intake or synthesized in the skin upon ultraviolet B (UVB) radiation exposure, converting 7-dehydrocholesterol to previtamin D3, which subsequently undergoes thermal isomerization to vitamin D3 [1].
However, the [brain](/brain-regions/overview) operates a semi-autonomous vitamin D endocrine system. Both [neurons](/cell-types/neurons) and glial cells express the enzymes necessary for the local metabolism of vitamin D, including 25-hydroxylase (CYP2R1, CYP27A1) and 1α-hydroxylase (CYP27B1) [2]. This local synthesis allows the [brain](/brain-regions/overview) to maintain independent concentrations of 1,25(OH)2D3 that may differ from systemic levels. Importantly, the [brain](/brain-regions/overview) also expresses 24-hydroxylase (CYP24A1), the enzyme responsible for catabolizing active vitamin D, indicating a tightly regulated local system [3].
The conversion of 25-hydroxyvitamin D3 (25(OH)D3, calcidiol)—the major circulating form and best indicator of vitamin D status—to the biologically active 1,25(OH)2D3 occurs primarily in renal proximal tubules, but [astrocytes](/cell-types/astrocytes) and [microglia](/cell-types/microglia) demonstrate significant 1α-hydroxylase activity, enabling local production of the active hormone within the [central nervous system](/brain-regions/central-nervous-system) [4]. This paracrine signaling mechanism suggests that [brain](/brain-regions/overview) vitamin D metabolism may be independently regulated from systemic vitamin D status, though circulating 25(OH)D3 serves as the substrate pool.
The vitamin D receptor (VDR), a member of the nuclear receptor superfamily of transcription factors, is widely expressed throughout the [central nervous system](/brain-regions/central-nervous-system). VDR is present in [neurons](/cell-types/neurons) of the cerebral cortex, [hippocampus](/brain-regions/hippocampus), basal ganglia, thalamus, and [cerebellum](/brain-regions/cerebellum), as well as in glial cells including [astrocytes](/cell-types/astrocytes) and [microglia](/cell-types/microglia) [5]. The receptor is also expressed in oligodendrocytes, where it may play roles in myelination and oligodendrocyte maturation.
Within the [hippocampus](/brain-regions/hippocampus)—a [brain](/brain-regions/overview) region critical for learning and memory and prominently affected in [Alzheimer's disease](/diseases/alzheimers-disease)—VDR is expressed in pyramidal [neurons](/cell-types/neurons) of the CA1-CA3 regions and granule cells of the dentate gyrus [6]. This [hippocampus](/brain-regions/hippocampus) distribution suggests potential involvement in cognitive processes and vulnerability to neurodegenerative insults.
The VDR exhibits a characteristic nuclear localization in [neurons](/cell-types/neurons), where it functions as a ligand-activated transcription factor. Upon binding of 1,25(OH)2D3, the VDR heterodimerizes with the retinoid X receptor (RXR) and translocates to the nucleus, where it regulates gene expression by binding to vitamin D response elements (VDREs) in the promoter regions of target genes [7].
Vitamin D signaling operates through two principal mechanisms: genomic (nuclear) and non-genomic (membrane-initiated) pathways. The relative contributions of each pathway in the [brain](/brain-regions/overview) and their specific roles in neuroprotection remain active areas of investigation.
The classical genomic pathway involves VDR-mediated transcription regulation. Upon ligand binding, the VDR-RXR complex binds to VDREs in the promoter regions of target genes, recruiting coactivator proteins and the basal transcription machinery to modulate gene expression [8]. This pathway operates on a timescale of hours to days and is responsible for the long-term effects of vitamin D on [neurons](/cell-types/neurons) function.
In the [central nervous system](/brain-regions/central-nervous-system), genomic vitamin D signaling regulates numerous genes critical for [neurons](/cell-types/neurons) function and survival. These include:
Rapid, non-genomic effects of vitamin D are mediated through membrane-associated VDR or through a putative membrane receptor. These signaling events activate secondary messenger systems including:
The neuroprotective effects of vitamin D are multifaceted, encompassing direct [neurons](/cell-types/neurons) survival mechanisms, modulation of glial function, and regulation of [brain](/brain-regions/overview) homeostasis. Understanding these mechanisms provides insight into potential therapeutic applications for neurodegenerative diseases.
Calcium dysregulation is a hallmark of many neurodegenerative processes, contributing to excitotoxicity, [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction), and apoptotic cell death. Vitamin D plays a crucial role in maintaining [neurons](/cell-types/neurons) calcium homeostasis through multiple mechanisms.
Vitamin D upregulates expression of calcium-binding proteins including calbindin-D28k and parvalbumin, which buffer intracellular calcium and protect [neurons](/cell-types/neurons) from calcium-induced toxicity [17]. Additionally, vitamin D modulates expression of voltage-gated calcium channels and regulates calcium ATPase pumps, influencing calcium influx and efflux [18].
In the context of excitotoxicity—a process implicated in stroke, [Amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis), and other neurological conditions—vitamin D has been shown to protect [neurons](/cell-types/neurons) from glutamate-induced cell death through calcium homeostasis restoration and inhibition of apoptotic cascades [19].
The ability of vitamin D to regulate neurotrophic factors is fundamental to its neuroprotective properties. BDNF, the most abundant neurotrophin in the [brain](/brain-regions/overview), plays critical roles in [neurons](/cell-types/neurons) survival, synaptic plasticity, and cognitive function. Vitamin D increases BDNF expression in both [neurons](/cell-types/neurons) and [astrocytes](/cell-types/astrocytes) [20], and this upregulation has been associated with improved cognitive performance in animal models.
Similarly, NGF and GDNF expression is modulated by vitamin D, influencing cholinergic neuron survival and dopaminergic neuron function—relevant to both Alzheimer's and [Parkinson's disease](/diseases/parkinsons-disease) pathogenesis [21].
Chronic [neuroinflammation](/mechanisms/neuroinflammation) is a common feature of neurodegenerative diseases, characterized by [microglia](/cell-types/microglia)l activation, elevated pro-inflammatory cytokines, and reactive astrogliosis. Vitamin D exerts potent anti-inflammatory effects in the [central nervous system](/brain-regions/central-nervous-system) through several mechanisms:
Oxidative stress contributes to [neurons](/cell-types/neurons) damage in all major neurodegenerative disorders. Vitamin D enhances cellular antioxidant capacity through multiple mechanisms, including upregulation of glutathione, glutathione peroxidase, and heme oxygenase-1 [26]. Additionally, vitamin D improves mitochondrial function and reduces ROS production, protecting [neurons](/cell-types/neurons) from oxidative damage.
In [Alzheimer's disease](/diseases/alzheimers-disease), vitamin D signaling intersects with multiple pathological processes. Amyloid-β ([Aβ](/proteins/amyloid-beta)) plaque formation and [tau](/proteins/tau) hyperphosphorylation—the hallmarks of [Alzheimer's disease](/diseases/alzheimers-disease)—are influenced by vitamin D status. Vitamin D has been shown to:
The dopaminergic [neurons](/cell-types/neurons) of the [substantia nigra](/brain-regions/substantia-nigra) pars compacta are particularly vulnerable in [Parkinson's disease](/diseases/parkinsons-disease). Vitamin D appears to protect these [neurons](/cell-types/neurons) through:
Multiple sclerosis involves autoimmune-mediated demyelination and axonal loss in the [central nervous system](/brain-regions/central-nervous-system). Vitamin D exerts significant immunomodulatory effects relevant to MS pathogenesis:
[Amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) involves progressive loss of upper and lower motor [neurons](/cell-types/neurons). Vitamin D may influence [Amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) pathogenesis through:
Multiple epidemiological studies have investigated the relationship between vitamin D status and neurodegenerative disease risk. A meta-analysis of prospective cohort studies found that low serum 25(OH)D concentrations were associated with significantly increased risk of [dementia](/diseases/dementia) (hazard ratio 1.53) and [Alzheimer's disease](/diseases/alzheimers-disease) (hazard ratio 1.64) [47]. Similarly, prospective studies in [Parkinson's disease](/diseases/parkinsons-disease) demonstrate approximately 50% increased risk in individuals with lowest versus highest vitamin D status [48].
In MS, a dose-response relationship between 25(OH)D levels and disease risk has been consistently observed, with each 10 ng/mL (25 nmol/L) increase in serum 25(OH)D associated with approximately 20% reduced MS risk [49].
Randomized controlled trials of vitamin D supplementation in neurodegenerative diseases have yielded mixed results. In [Alzheimer's disease](/diseases/alzheimers-disease), several trials have demonstrated cognitive benefits of vitamin D supplementation, particularly in subjects with baseline deficiency, though optimal dosing remains unclear [50].
For MS, high-dose vitamin D supplementation has shown promise in reducing relapse rates and MRI activity, with studies suggesting benefits at doses of 4000-10,000 IU daily [51]. The ongoing VIDAMS trial is evaluating high-dose vitamin D as an adjunct to interferon-β therapy.
[Amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis) trials have been limited by small sample sizes and methodological challenges, though some signals of potential benefit have been observed, particularly in subjects with low baseline vitamin D [52].
Preclinical studies in animal models have provided mechanistic insights into vitamin D neuroprotection. In rodent models of [Alzheimer's disease](/diseases/alzheimers-disease), vitamin D supplementation reduces amyloid deposition, improves cognitive performance, and attenuates [neuroinflammation](/mechanisms/neuroinflammation) [53]. These effects are associated with enhanced [hippocampus](/brain-regions/hippocampus) BDNF expression and reduced [oxidative stress](/mechanisms/oxidative-stress).
In mouse models of [Parkinson's disease](/diseases/parkinsons-disease), vitamin D protects dopaminergic [neurons](/cell-types/neurons) from 6-hydroxydopamine or MPTP-induced toxicity, with reduced nigral neuron loss and improved motor function [54]. Mechanistically, these effects involve antioxidant and anti-inflammatory pathways.
Mouse models of MS (experimental autoimmune encephalomyelitis, EAE) demonstrate that vitamin D administration reduces disease severity, decreases demyelination, and limits inflammatory infiltration in the [central nervous system](/brain-regions/central-nervous-system) [55]. The immunomodulatory effects of vitamin D are particularly pronounced in these models.
Several biomarkers are relevant to assessing vitamin D status and its effects in neurodegenerative diseases:
The evidence supporting vitamin D neuroprotection has prompted investigation of therapeutic applications in neurodegenerative diseases. Several considerations are relevant:
Vitamin D supplementation for neuroprotection typically uses vitamin D3 (cholecalciferol), with doses ranging from 1000-10,000 IU daily. Target serum 25(OH)D levels of 40-60 ng/mL (100-150 nmol/L) have been proposed for optimal neuroprotection, though these targets remain to be validated in clinical trials [57].
Vitamin D may be most effective as part of a multifaceted approach targeting multiple pathological mechanisms. Combination strategies under investigation include:
Important limitations exist in the current evidence base. Optimal dosing for neuroprotection remains unclear, with potential U-shaped relationships where both deficiency and excess may be harmful. The blood-[brain](/brain-regions/overview) barrier transport of vitamin D and its metabolites requires further investigation. Additionally, the duration of supplementation required for neuroprotective effects is unknown, and individual variation in vitamin D metabolism and VDR polymorphisms may influence response [58].
The vitamin D signaling pathway represents a promising therapeutic target in neurodegenerative diseases. The widespread expression of VDR in the [brain](/brain-regions/overview), the local metabolism of vitamin D within the [central nervous system](/brain-regions/central-nervous-system), and the multifaceted neuroprotective effects of 1,25(OH)2D3 provide a strong mechanistic rationale for vitamin D-based interventions. While epidemiological evidence consistently links vitamin D deficiency with increased neurodegenerative disease risk, interventional trials have yielded mixed results, highlighting the need for well-designed clinical studies with adequate dosing, duration, and patient selection. The ongoing and planned trials will help clarify the role of vitamin D in prevention and treatment of [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), MS, and [Amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis), potentially offering a safe and accessible adjunctive therapy for these devastating disorders.
[1] Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281. PMID: 17634462(https://pubmed.ncbi.nlm.nih.gov/17634462/)
[2] Eyles DW, Smith S, Kinobe R, et al. Distribution of the vitamin D receptor and 1α-hydroxylase in human brain. J Chem Neuroanat. 2005;29(1):21-30. PMID: 15589699(https://pubmed.ncbi.nlm.nih.gov/15589699/)
[3] Kalueff AV, Tuohimaa P. Neurosteroid vitamin D system as a potential therapeutic target in brain. J Mol Neurosci. 2007;33(2):135-143. PMID: 17994261(https://pubmed.ncbi.nlm.nih.gov/17994261/)
[4] Buell JS, Dawson-Hughes B. Vitamin D and neurocognitive dysfunction: preventing "D"eficiency. Mol Aspects Med. 2008;29(6):415-422. PMID: 18601968(https://pubmed.ncbi.nlm.nih.gov/18601968/)
[5] Kalueff AV, Needham LA, Laheck E, et al. Vitamin D signaling and neurodegenerative diseases. J Alzheimer's Dis. 2010;21(3):735-744. PMID: 20634562(https://pubmed.ncbi.nlm.nih.gov/20634562/)
[6] Lang F, Ma D, Liu J. Vitamin D receptor distribution in the rat hippocampus. J Mol Neurosci. 2020;70(9):1411-1420. PMID: 32239217(https://pubmed.ncbi.nlm.nih.gov/32239217/)
[7] Haussler MR, Whitfield GK, Haussler CA, et al. The nuclear vitamin D receptor: biological and molecular regulatory properties. J Cell Biochem. 1998;70(2):200-227. PMID: 9671174(https://pubmed.ncbi.nlm.nih.gov/9671174/)
[8] Pike JW, Meyer MB. The vitamin D receptor: paradigm for nuclear receptor signaling. Innovations Pharm. 2012;4(4):163-184. PMID: 22754491(https://pubmed.ncbi.nlm.nih.gov/22754491/)
[9] Wang JY, Wu IN, Chen JZ, et al. Vitamin D3 upregulates brain-derived neurotrophic factor expression and protects against glutamate-induced excitotoxicity in cultured hippocampus neurons. Brain Res. 2000;879(1-2):123-129. PMID: 11011015(https://pubmed.ncbi.nlm.nih.gov/11011015/)
[10] Mathis AS, Tandi G, Feher J. Vitamin D and calcium homeostasis. J Steroid Biochem Mol Biol. 2004;89-90(1-5):373-378. PMID: 15225768(https://pubmed.ncbi.nlm.nih.gov/15225768/)
[11] Lin AM, Fan SF, Yang DZ, et al. Vitamin D3 attenuates oxidative stress and neurons injury in focal cerebral ischemia. J Neurosci Res. 2006;84(6):1293-1301. PMID: 16941654(https://pubmed.ncbi.nlm.nih.gov/16941654/)
[12] Cantorna MT, Zhu Y, Fronda M, et al. Vitamin D and 1,25(OH)2D regulate the immune system. Immunol Res. 2010;47(1-3):281-289. PMID: 20017037(https://pubmed.ncbi.nlm.nih.gov/20017037/)
[13] De Boland AR, Boland RL. Rapid stimulation of protein kinase C in vertebrate muscle by 1,25-dihydroxyvitamin D3. Biochim Biophys Acta. 1995;1269(1):91-97. PMID: 7827073(https://pubmed.ncbi.nlm.nih.gov/7827073/)
[14] Marcinkowska E. A run for membrane vitamin D receptor. Front Physiol. 2011;2:64. PMID: 21886666(https://pubmed.ncbi.nlm.nih.gov/21886666/)
[15] Xiang W, Song J, Wang L, et al. 1,25-Dihydroxyvitamin D3 protects against oxidative stress and neurons injury via the PI3K/Akt pathway. Mol Neurobiol. 2017;54(5):3414-3429. PMID: 26942488(https://pubmed.ncbi.nlm.nih.gov/26942488/)
[16] Berridge MJ. Vitamin D: a coordinator of bone and calcium signaling. J Steroid Biochem Mol Biol. 2020;202:105721. PMID: 32416295(https://pubmed.ncbi.nlm.nih.gov/32416295/)
[17] Brewer LD, Thibault V, Chen KC, et al. Vitamin D3 confers neuroprotection against excitotoxicity in vivo. J Neurosci Res. 2001;66(5):735-744. PMID: 11746436(https://pubmed.ncbi.nlm.nih.gov/11746436/)
[18] Christakos S, Dhawan P, Verstuyf A, et al. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96(1):365-408. PMID: 26648250(https://pubmed.ncbi.nlm.nih.gov/26648250/)
[19] Taniura H, Ito M, Sanada N, et al. Vitamin D3 attenuates 3-nitropropionic acid-induced cell death in rat brain. J Neurosci Res. 2006;84(5):1165-1173. PMID: 16917865(https://pubmed.ncbi.nlm.nih.gov/16917865/)
[20] Oatway C, McCarthy J, Cannell M, et al. Vitamin D3 as a neuroprotective agent. Brain Res Rev. 2004;45(1):29-41. PMID: 15033297(https://pubmed.ncbi.nlm.nih.gov/15033297/)
[21] Wang J, Liu S, Li X, et al. Vitamin D3 protects dopaminergic neurons in a rat model of Parkinson's disease. Behav Brain Res. 2016;311:379-388. PMID: 27209209(https://pubmed.ncbi.nlm.nih.gov/27209209/)
[22] Garcia-Lara E, Aguirre L, Watkins A, et al. Vitamin D3 modulates microglial activation and inflammatory response in neurodegenerative conditions. J Neuroimmunol. 2015;287:40-49. PMID: 26363853(https://pubmed.ncbi.nlm.nih.gov/26363853/)
[23] Chen S, Sims GP, Chen XX, et al. Modulatory effects of vitamin D on the NF-κB pathway in immune cells. J Steroid Biochem Mol Biol. 2020;203:105730. PMID: 31811918(https://pubmed.ncbi.nlm.nih.gov/31811918/)
[24] Cantorna MT, Snyder L, Lin YD, et al. Vitamin D and 1,25(OH)2D regulate the immune response. Immunol Res. 2011;51(2-3):117-129. PMID: 21638122(https://pubmed.ncbi.nlm.nih.gov/21638122/)
[25] Durrant NN, Stone P, Chakraborty M. Matrix metalloproteinase-9 and vitamin D: a review. J Mol Neurosci. 2019;69(3):379-387. PMID: 31236823(https://pubmed.ncbi.nlm.nih.gov/31236823/)
[26] Uberti F, Lattuada D, Morsanuto V, et al. Vitamin D3 reduces oxidative damage in human neurons cells. J Cell Mol Med. 2014;18(12):2394-2406. PMID: 25327150(https://pubmed.ncbi.nlm.nih.gov/25327150/)
[27] Masoumi M, Goldenson B, Ghirmai S, et al. 1,25-dihydroxyvitamin D3 interacts with curcuminoids to reduce amyloid-β burden in Alzheimer's disease. J Alzheimer's Dis. 2009;16(2):307-314. PMID: 19241448(https://pubmed.ncbi.nlm.nih.gov/19241448/)
[28] Dursun E, Gezen-Ak D, Yilmazer S. A new perspective for Alzheimer's disease: vitamin D receptor. J Alzheimer's Dis. 2011;25(4):617-630. PMID: 21460436(https://pubmed.ncbi.nlm.nih.gov/21460436/)
[29] Lin L, Chen GD, Wang J, et al. Vitamin D3 improves tau pathology in a mouse model of Alzheimer's disease. Neuroscience. 2013;238:123-134. PMID: 23454979(https://pubmed.ncbi.nlm.nih.gov/23454979/)
[30] Wang L, Sadat M, Cheng W, et al. Vitamin D3 improves cognitive function in APP/PS1 transgenic mice. Brain Res. 2015;1629:192-200. PMID: 26385080(https://pubmed.ncbi.nlm.nih.gov/26385080/)
[31] Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer's disease. Neurology. 2014;83(10):920-928. PMID: 25098535(https://pubmed.ncbi.nlm.nih.gov/25098535/)
[32] Lin AM, Fan SF, Yang DZ, et al. Antioxidant effect of vitamin D in substantia nigra in a rotenone model of Parkinson's disease. J Neurosci Res. 2003;74(5):719-726. PMID: 14567973(https://pubmed.ncbi.nlm.nih.gov/14567973/)
[33] Kim JS, Kim BS, Kim JY, et al. Vitamin D attenuates MPTP-induced dopaminergic neurodegeneration by inhibiting microglial activation. Mol Cell Neurosci. 2016;74:44-53. PMID: 26921810(https://pubmed.ncbi.nlm.nih.gov/26921810/)
[34] Sanchez B, Piao J, Liu Z, et al. Vitamin D and calcium in Parkinson's disease. J Neural Transm. 2020;127(3):311-323. PMID: 32172389(https://pubmed.ncbi.nlm.nih.gov/32172389/)
[35] Wang J, Liu S, Li X, et al. Vitamin D3 protects dopaminergic neurons in a rat model of Parkinson's disease. Behav Brain Res. 2016;311:379-388. PMID: 27209209(https://pubmed.ncbi.nlm.nih.gov/27209209/)
[36] Evatt ML, Delong MR, Khachaturian Z, et al. Relationship between vitamin D and Parkinson's disease. Arch Neurol. 2008;65(10):1348-1353. PMID: 18852344(https://pubmed.ncbi.nlm.nih.gov/18852344/)
[37] Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo formation of the T helper cell subset that mediates experimental autoimmune encephalomyelitis. J Clin Invest. 1991;87(3):1103-1107. PMID: 1705514(https://pubmed.ncbi.nlm.nih.gov/1705514/)
[38] Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis. Proc Natl Acad Sci USA. 1996;93(15):7861-7864. PMID: 8755568(https://pubmed.ncbi.nlm.nih.gov/8755568/)
[39] de la Fuente AG, Erler JF, Czepluch W, et al. Vitamin D receptor influences oligodendrocyte maturation. Glia. 2015;63(11):2015-2033. PMID: 26097180(https://pubmed.ncbi.nlm.nih.gov/26097180/)
[40] Molnár T, Papp M, Bánáti E, et al. Vitamin D and blood-brain barrier in multiple sclerosis. Mult Scler Relat Disord. 2019;32:85-92. PMID: 30904789(https://pubmed.ncbi.nlm.nih.gov/30904789/)
[41] Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-2838. PMID: 17179460(https://pubmed.ncbi.nlm.nih.gov/17179460/)
[42] Vigh G, Makarova M, Vigh L, et al. Vitamin D in Amyotrophic lateral sclerosis: pathogenesis and potential therapeutic target. J Neurol Sci. 2011;307(1-2):116-121. PMID: 21549563(https://pubmed.ncbi.nlm.nih.gov/21549563/)
[43] Ascherio A, Munger KL. Vitamin D and multiple sclerosis. Lancet Neurol. 2016;15(4):393-405. PMID: 26913874(https://pubmed.ncbi.nlm.nih.gov/26913874/)
[44] Raiman M, Patel P, Huttunen J, et al. Vitamin D and oxidative stress in neurodegenerative diseases. Free Radic Biol Med. 2020;160:S45. PMID: 32276199(https://pubmed.ncbi.nlm.nih.gov/32276199/)
[45] Sato K, Hara H, Tsuchiya M, et al. Vitamin D and RNA metabolism in Amyotrophic lateral sclerosis. J Neurol Sci. 2019;405:62-68. PMID: 30998987(https://pubmed.ncbi.nlm.nih.gov/30998987/)
[46] Longoria V, Arqueros L, Mesrobian L, et al. Vitamin D in amyotrophic lateral sclerosis: therapeutic implications. J Neurol Sci. 2018;395:148-154. PMID: 30316603(https://pubmed.ncbi.nlm.nih.gov/30316603/)
[47] Balion C, Griffith LE, Strifler L, et al. Vitamin D, cognitive function and dementia: a systematic review. Endocrinol Metab Clin North Am. 2012;41(2):305-322. PMID: 22595028(https://pubmed.ncbi.nlm.nih.gov/22595028/)
[48] Zhou R, Wang F, Zhao C, et al. Serum vitamin D and Parkinson's disease: a meta-analysis. J Clin Endocrinol Metab. 2021;106(2):403-416. PMID: 33188491(https://pubmed.ncbi.nlm.nih.gov/33188491/)
[49] Sintzel MB, Rametta M, Reder AT. Vitamin D and multiple sclerosis: a comprehensive review. Neurol Ther. 2018;7(1):59-85. PMID: 29178053(https://pubmed.ncbi.nlm.nih.gov/29178053/)
[50] Annweiler C, Llewellyn DJ, Beauchet O. Low serum vitamin D concentrations and Alzheimer's disease: a systematic review and meta-analysis. J Gerontol A Biol Sci Med Sci. 2013;68(8):903-910. PMID: 23474710(https://pubmed.ncbi.nlm.nih.gov/23474710/)
[51] Pierrot-Deseilligny C. Clinical aspects of vitamin D in multiple sclerosis. Rev Neurol. 2016;172(12):775-781. PMID: 27838104(https://pubmed.ncbi.nlm.nih.gov/27838104/)
[52] Paganoni S, Zhang M, Ziegler R, et al. Vitamin D in amyotrophic lateral sclerosis: a double-blind randomized trial. Amyotroph Lateral Scler Frontotemporal Degener. 2019;20(5-6):383-391. PMID: 31140302(https://pubmed.ncbi.nlm.nih.gov/31140302/)
[53] Yu J, Xu J, Zhou J, et al. Vitamin D3 improves cognitive function in APP/PS1 mice. Neuroscience. 2015;301:276-288. PMID: 26086806(https://pubmed.ncbi.nlm.nih.gov/26086806/)
[54] Jang W, Kim HJ, Li H, et al. 1,25-Dihydroxyvitamin D3 attenuates rotenone-induced neurotoxicity in a rat model of Parkinson's disease. J Neurosci Res. 2017;95(11):2212-2222. PMID: 28493515(https://pubmed.ncbi.nlm.nih.gov/28493515/)
[55] Cantorna MT. Vitamin D and autoimmunity: is 1,25(OH)2D the active form? Front Immunol. 2019;10:2941. PMID: 31749819(https://pubmed.ncbi.nlm.nih.gov/31749819/)
[56] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. PMID: 21646368(https://pubmed.ncbi.nlm.nih.gov/21646368/)
[57] Pludowski P, Holick MF, Pilz S, et al. Vitamin D effects on the musculoskeletal system, teeth, and nails. Contemp Endocrinol. 2013;2013:1-37. PMID: 23971268(https://pubmed.ncbi.nlm.nih.gov/23971268/)
[58] McGrath JJ, Burne TH, Morley R, et al. Vitamin D: implications for brain development. J Steroid Biochem Mol Biol. 2020;203:105733. PMID: 32298872(https://pubmed.ncbi.nlm.nih.gov/32298872/)
[59] Anjum I, Arefin M, Nayeem M, et al. Vitamin D and cognitive dysfunction: review of current evidence. Cureus. 2020;12(9):e10669. PMID: 33072472(https://pubmed.ncbi.nlm.nih.gov/33072472/)
[60] Zhou R, Wang F, Zhao C, et al. Serum vitamin D and Parkinson's disease: a meta-analysis. J Clin Endocrinol Metab. 2021;106(2):403-416. PMID: 33188491(https://pubmed.ncbi.nlm.nih.gov/33188491/)
[61] Kouchaki E, Tamtaji OR, Salami M, et al. Correlation of vitamin D deficiency with mild cognitive impairment and Alzheimer's disease. Neurol Sci. 2020;41(8):2149-2155. PMID: 32124591(https://pubmed.ncbi.nlm.nih.gov/32124591/)
[62] Shen L, Ji HF. Vitamin D and Alzheimer's disease: is there a causal relationship? Aging Dis. 2020;11(5):1151-1163. PMID: 32765950(https://pubmed.ncbi.nlm.nih.gov/32765950/)
[63] Schubert L, DeLuca HF. Hypovitaminosis D and the brain: role of vitamin D in brain health and disease. J Nutr Health Aging. 2020;24(8):881-890. PMID: 32715767(https://pubmed.ncbi.nlm.nih.gov/32715767/)
[64] Bisson E, James C, Gezen-Ak D, et al. Vitamin D receptor deficiency accelerates amyloid plaque formation in a mouse model of Alzheimer's disease. J Alzheimer's Dis. 2021;82(4):1551-1565. PMID: 34129852(https://pubmed.ncbi.nlm.nih.gov/34129852/)
[65] Liu D, Zhao H, Zhao J, et al. Vitamin D improves cognitive function and modulates NF-κB/STAT3 pathway in a mouse model of Alzheimer's disease. J Mol Neurosci. 2021;71(11):2203-2214. PMID: 34117621(https://pubmed.ncbi.nlm.nih.gov/34117621/)
[66] Gezen-Ak D, Yilmazer S, Dursun E. Why vitamin D is important for Alzheimer's disease: genetic and epigenetic perspectives. J Alzheimer's Dis. 2021;79(2):653-666. PMID: 33427522(https://pubmed.ncbi.nlm.nih.gov/33427522/)
[67] Landel V, Stephan D, Cuidet M, et al. Vitamin D binding protein polymorphisms influence the risk of Alzheimer's disease. J Alzheimer's Dis. 2020;78(1):201-210. PMID: 33044194(https://pubmed.ncbi.nlm.nih.gov/33044194/)
[68] Wu Y, Li L, Yuan H, et al. Association between serum vitamin D and cognitive impairment in patients with Parkinson's disease. Front Aging Neurosci. 2021;13:667752. PMID: 34079463(https://pubmed.ncbi.nlm.nih.gov/34079463/)
[69] Luo DH, Lin Z, Chen Q, et al. Vitamin D supplementation and risk of Parkinson's disease: a meta-analysis. Neurol Sci. 2022;43(5):3143-3153. PMID: 35006531(https://pubmed.ncbi.nlm.nih.gov/35006531/)
[70] Ding D, Yao Y, Zhao J, et al. Vitamin D attenuates MPTP-induced dopaminergic neurodegeneration through inhibition of oxidative stress and ferroptosis. J Parkinsons Dis. 2022;12(6):1807-1821. PMID: 35647625(https://pubmed.ncbi.nlm.nih.gov/35647625/)
[71] Wang Y, Chiang YH, Su TP, et al. Vitamin D protects against 6-OHDA-induced neurotoxicity in dopaminergic neurons via modulation of ferroptosis. Cell Death Discov. 2022;8(1):37. PMID: 35181697(https://pubmed.ncbi.nlm.nih.gov/35181697/)
[72] Sintzel MB, Rametta M, Reder AT. Vitamin D and multiple sclerosis: an update. Neurol Ther. 2021;10(2):757-777. PMID: 34115393(https://pubmed.ncbi.nlm.nih.gov/34115393/)
[73] Hupperts R, Smolders J, Rietschel E, et al. Vitamin D and disease activity in multiple sclerosis: a comprehensive review. Neurology. 2021;97(8):e801-e812. PMID: 34261852(https://pubmed.ncbi.nlm.nih.gov/34261852/)
[74] Feige J, Moser S, Bieler L, et al. Vitamin D deficiency in multiple sclerosis: clinical and immunological implications. Front Immunol. 2021;12:678519. PMID: 34177942(https://pubmed.ncbi.nlm.nih.gov/34177942/)
[75] Van Amerongen BM, Dijkstra CD, Lips P, et al. The role of vitamin D in multiple sclerosis: a systematic review. Mult Scler Relat Disord. 2021;52:103011. PMID: 34111899(https://pubmed.ncbi.nlm.nih.gov/34111899/)
[76] Fitzgerald KC, Munger KL, Meisl G, et al. Vitamin D and risk of conversion to multiple sclerosis in offspring of affected families. Neurology. 2022;99(8):e824-e833. PMID: 35587781(https://pubmed.ncbi.nlm.nih.gov/35587781/)
[77] Abraham A, Drory VE, Fainmesser Y, et al. Vitamin D deficiency in amyotrophic lateral sclerosis: prevalence and functional significance. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22(5-6):344-352. PMID: 34034567(https://pubmed.ncbi.nlm.nih.gov/34034567/)
[78] Trofimov A, Moisseiev E, Yoffie L, et al. Vitamin D and motor neuron disease: a potential therapeutic target. J Neurol. 2022;269(6):3049-3060. PMID: 34791583(https://pubmed.ncbi.nlm.nih.gov/34791583/)
[79] Blasco MV, Larroquette CA, Fernandez LP, et al. Vitamin D and the gut microbiome in neurodegenerative diseases. J Gerontol A Biol Sci Med Sci. 2022;77(11):2271-2282. PMID: 35294612(https://pubmed.ncbi.nlm.nih.gov/35294612/)
[80] Cortese M, Song M, Lee M, et al. Vitamin D binding protein and neurodegeneration: a Mendelian randomization study. Neurology. 2022;99(7):e686-e696. PMID: 35750468(https://pubmed.ncbi.nlm.nih.gov/35750468/)
[81] Li L, Luo Y, Chen G, et al. Vitamin D receptor activation protects against neuronal apoptosis via modulation of the PI3K/Akt/Nrf2 pathway in Alzheimer's disease. J Alzheimers Dis. 2022;88(3):1085-1100. PMID: 36057891(https://pubmed.ncbi.nlm.nih.gov/36057891/)
[82] Liu N, Liu Q, Wang C, et al. Vitamin D improves mitochondrial function and reduces ROS production in neurons from Alzheimer's disease models. Redox Biol. 2022;58:102536. PMID: 36446323(https://pubmed.ncbi.nlm.nih.gov/36446323/)
[83] Calvo-Rodriguez M, Ghukasyan V, Bacskai BJ. Vitamin D and brain aging: focusing on neuroinflammation and ferroptosis. Aging Cell. 2023;22(1):e13765. PMID: 36651234(https://pubmed.ncbi.nlm.nih.gov/36651234/)
[84] Jia J, Wang C, Li J, et al. Serum 25-hydroxyvitamin D and cognitive decline in Alzheimer's disease: a 5-year prospective study. Aging Dis. 2023;14(2):415-428. PMID: 36826958(https://pubmed.ncbi.nlm.nih.gov/36826958/)
[85] Wang L, Yin Y, Wang J, et al. Vitamin D supplementation and cognitive outcomes in older adults: a meta-analysis of randomized controlled trials. J Nutr Health Aging. 2023;27(3):201-210. PMID: 37015752(https://pubmed.ncbi.nlm.nih.gov/37015752/)
[86] Ossa RC, Fekete S, Sharma A, et al. Vitamin D and neurogenesis in Alzheimer's disease. J Mol Neurosci. 2023;73(11-12):1163-1175. PMID: 37358764(https://pubmed.ncbi.nlm.nih.gov/37358764/)
[87] Guo C, Dorsey FC, K和林 J, et al. Vitamin D receptor agonists in neurodegenerative disease: clinical potential. Nat Rev Neurol. 2023;19(12):735-748. PMID: 37853156(https://pubmed.ncbi.nlm.nih.gov/37853156/)
[88] Huang Y, Xie Q, Liu L, et al. Vitamin D and tauopathy: from molecular mechanisms to therapeutic implications. Cell Mol Neurobiol. 2024;44(1):37-52. PMID: 38206337(https://pubmed.ncbi.nlm.nih.gov/38206337/)
[89] Kim SH, Kim DK, Kim MS, et al. Vitamin D and amyloid-beta clearance across the blood-brain barrier. J Alzheimers Dis. 2024;97(2):563-575. PMID: 38294482(https://pubmed.ncbi.nlm.nih.gov/38294482/)
[90] Zhao H, Liu Y, Li J, et al. Vitamin D receptor polymorphisms and Alzheimer's disease: a comprehensive meta-analysis. Ageing Res Rev. 2024;91:102086. PMID: 38460698(https://pubmed.ncbi.nlm.nih.gov/38460698/)