Genomic and Nongenomic Signaling Induced by 1α,25(OH)2-Vitamin D3 Promotes the Recovery of Amyloid-β Phagocytosis by Alzheimer's Disease Macrophages

Mizwicki, Mathew T.; Menegaz, Danusa; Zhang, Jun; Barrientos‐Durán, Antonio; Tse, Stephen; Cashman, John R.; Griffin, Patrick R.; Fiala, Milan

doi:10.3233/jad-2012-110560

Cited by 116 publications

(76 citation statements)

References 49 publications

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“…Importantly, Annweiler et al (2012a) showed the association of elevated serum 25OHD concentration with a lower risk of mild cognitive impairment (MCI) and the association of low 25OHD concentrations with MCI status in older non-demented people with subjective memory complaint, suggesting that hypovitaminosis D may participate in the dementia process from prodromal stages. Recent remarkable studies showed that vitamin D strongly stimulated phagocytosis and clearance of beta amyloid while protecting against apoptosis in AD patients' macrophages (Masoumi et al 2009;Mizwicki et al 2012). Fiala and Mizwicki (2011) suggested that increased consumption of vitamin D and fish oil could prevent neurodegeneration in some subjects by maintaining adequate endocrine, paracrine, and/or autocrine production of vitamin D and docosahexaenoic acid (DHA)-derived lipidic modulators.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Gene Haplotype Is Associated with Late-Onset Alzheimer's Disease

Gezen-Ak

Dursun

Bılgıç

et al. 2012

Tohoku J. Exp. Med.

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Vitamin D 3 is a neurosteroid that mediates its effects via the vitamin D receptor (VDR). The VDR gene is located on chromosome 12q13 and consists of 9 exons. VDR contains the DNA-binding site encoded by exons 2 and 3 and the ligand-binding site encoded by exons 4 -9. Our earlier study showed that the ApaI polymorphic site of the VDR gene is associated with late-onset Alzheimer's disease (AD). Here, we investigated the association between additional polymorphisms of the VDR gene and AD using the same samples. Two single nucleotide polymorphisms (SNPs) in intron 8 (BsmI and Tru9I polymorphisms) and one in exon 2 (FokI polymorphism) of the VDR gene were examined in up to 108 AD patients and 115 age-matched controls. Genotypes were determined with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Haplotype analysis also included the previously studied polymorphic sites that were recognized by TaqI (in exon 9) and ApaI (in intron 8) restriction enzymes. There was no significant difference between AD patients and controls when their genotypes for BsmI, Tru9I and FokI polymorphic sites were compared. However, the frequency of "TaubF" haplotype (alleles of TaqI, ApaI, Tru9I, BsmI and FokI, respectively), which was determined by analyzing 5 polymorphisms together, was significantly higher in the AD patient group, suggesting that this haplotype is a risk factor in AD. Our results point out a possible link between AD and certain VDR polymorphisms and indicate that individuals with these polymorphisms might be vulnerable to AD.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor Gene Haplotype Is Associated with Late-Onset Alzheimer's Disease

Gezen-Ak

Dursun

Bılgıç

et al. 2012

Tohoku J. Exp. Med.

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“…Therefore, in line with Buell and Dawson-Hughes [169], calcium concentrations are not likely to vary in the different haplotypes, indicating a protective effect on the brain, beyond the calcium homeostasis. Thus, in the Alzheimer disease culture models, VDH stimulates the amyloid plaques [170,171], supporting the phagocytosis induced by macrophages of a soluble amyloid beta protein [171,172], and reduces the inflammation response induced by amyloid deposition [21]. Lipopolysaccharide-induced levels of mRNA encoding for macrophage colony stimulating factors and tumor necrosis factors in cultured astrocytes are partially reduced after vitamin D treatment [21].…”

Section: Vitamin D Deficiency and Neurodegenerative Diseasesmentioning

confidence: 99%

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact

Moretti

Morelli

Caruso

2018

IJMS

115

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It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and maturation, through the control operation of growing factors synthesis (i.e., neural growth factor [NGF] and glial cell line-derived growth factor (GDNF), the trafficking of the septohippocampal pathway, and the control of the synthesis process of different neuromodulators (such as acetylcholine [Ach], dopamine [DA], and gamma-aminobutyric [GABA]). Based on these assumptions, we have written this review to summarize the potential role of vitamin D in neurological pathologies. This work could be titanic and the results might have been very fuzzy and even incoherent had we not conjectured to taper our first intentions and devoted our interests towards three mainstreams, demyelinating pathologies, vascular syndromes, and neurodegeneration. As a result of the lack of useful therapeutic options, apart from the disease-modifying strategies, the role of different risk factors should be investigated in neurology, as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long-term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.

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“…The first class, based on extending the aliphatic side-chain of 1,25D3, function to sterically disrupt helix 12 closure (Carlberg 2004); the second, based on an adamantyl side-chain chemistry, more subtly disrupt helix 12 closure (Igarashi et al 2007; Nakabayashi et al 2008); and the third class, which was first to be discovered, was generated by removing the chiral end of one of the terminal side-chain metabolites of 1,25D3, to generate (23S)-1α(OH)-vitamin D 3 -26,23-lactone (MK)] (Miura et al 1999). Similar to the adamantyl-based antagonists, MK does not sterically displace helix 12 from the active position (Mizwicki et al 2009a) and does mimic 1,25D3 in its’ ability to stabilize other regions of the VDR LBD (Kakuda et al 2010; Mizwicki et al 2012). MK is a unique NR antagonist because it can be converted into a VDR superagonist (i.e.…”

Section: Introductionmentioning

confidence: 99%

Agonist and antagonist binding to the nuclear vitamin D receptor: dynamics, mutation effects and functional implications

Yaghmaei

Roberts

et al. 2013

In Silico Pharmacol.

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PurposeThe thermodynamically favored complex between the nuclear vitamin D receptor (VDR) and 1α,25(OH)2-vitamin D3 (1,25D3) triggers a shift in equilibrium to favor VDR binding to DNA, heterodimerization with the nuclear retinoid x receptor (RXR) and subsequent regulation of gene transcription. The key amino acids and structural requirements governing VDR binding to nuclear coactivators (NCoA) are well defined. Yet very little is understood about the internal changes in amino acid flexibility underpinning the control of ligand affinity, helix 12 conformation and function. Herein, we use molecular dynamics (MD) to study how the backbone and side-chain flexibility of the VDR differs when a) complexed to 1α,25(OH)2-vitamin D3 (1,25D3, agonist) and (23S),25-dehydro-1α(OH)-vitamin D3-26,23-lactone (MK, antagonist); b) residues that form hydrogen bonds with the C25-OH (H305 and H397) of 1,25D3 are mutated to phenylalanine; c) helix 12 conformation is changed and ligand is removed; and d) x-ray water near the C1- and C3-OH groups of 1,25D3 are present or replaced with explicit solvent.MethodsWe performed molecular dynamic simulations on the apo- and holo-VDRs and used T-Analyst to monitor the changes in the backbone and side-chain flexibility of residues that form regions of the VDR ligand binding pocket (LBP), NCoA surface and control helix 12 conformation.ResultsThe VDR-1,25D3 and VDR-MK MD simulations demonstrate that 1,25D3 and MK induce highly similar changes in backbone and side-chain flexibility in residues that form the LBP. MK however did increase the backbone and side-chain flexibility of L404 and R274 respectively. MK also induced expansion of the VDR charge clamp (i.e. NCoA surface) and weakened the intramolecular interaction between H305---V418 (helix 12) and TYR401 (helix 11). In VDR_FF, MK induced a generally more rigid LBP and stronger interaction between F397 and F422 than 1,25D3, and reduced the flexibility of the R274 side-chain. Lastly the VDR MD simulations indicate that R274 can sample multiple conformations in the presence of ligand. When the R274 is extended, the β-OH group of 1,25D3 lies proximal to the backbone carbonyl oxygen of R274 and the side-chain forms H-bonds with hinge domain residues. This differs from the x-ray, kinked geometry, where the side-chain forms an H-bond with the 1α-OH group. Furthermore, 1,25D3, but not MK was observed to stabilize the x-ray geometry of R274 during the > 30 ns MD runs.ConclusionsThe MD methodology applied herein provides an in silico foundation to be expanded upon to better understand the intrinsic flexibility of the VDR and better understand key side-chain and backbone movements involved in the bimolecular interaction between the VDR and its’ ligands.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-9616-1-2) contains supplementary material, which is available to authorized users.

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Genomic and Nongenomic Signaling Induced by 1α,25(OH)2-Vitamin D3 Promotes the Recovery of Amyloid-β Phagocytosis by Alzheimer's Disease Macrophages

Cited by 116 publications

References 49 publications

Vitamin D Receptor Gene Haplotype Is Associated with Late-Onset Alzheimer's Disease

Vitamin D Receptor Gene Haplotype Is Associated with Late-Onset Alzheimer's Disease

Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact

Agonist and antagonist binding to the nuclear vitamin D receptor: dynamics, mutation effects and functional implications

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