Genetic variants of vitamin D metabolism-related DHCR7/NADSYN1 locus and CYP2R1 gene are associated with clinical features of Parkinson's disease.

PURPOSE/AIM OF THE STUDY: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Vitamin D deficiency is suggested to be related to PD. A genome-wide association study indicated that genes involved in vitamin D metabolism affect vitamin D levels. Among these genes, single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) and vitamin D binding protein (VDBP/GC) genes have also been demonstrated to be associated with PD risk. Our aim was to investigate the relevance of SNPs within the 7-dehydrocholesterol reductase/nicotinamide adenine dinucleotide synthetase 1 (DHCR7/NADSYN1) locus and vitamin D 25-hydroxylase (CYP2R1) gene, which encode important enzymes that play a role in the vitamin D synthesis pathway, with PD and its clinical features. MATERIALS AND METHODS: Genotypes of 382 PD patients and 240 cognitively healthy individuals were evaluated by a LightSNiP assay for a total of 10 SNPs within the DHCR7/NADSYN1 locus and CYP2R1 gene. RESULTS: There were no significant differences in the allele and genotype distributions of any of the SNPs between any patient groups and healthy subjects. However, our results indicated that all of the SNPs within the DHCR7/NADSYN1 locus and CYP2R1 gene, except rs1993116, were associated with clinical motor features of PD including initial predominant symptom, freezing of gait (FoG) and falls as well as disease stage and duration of the disease. CONCLUSIONS: In conclusion, genetic variants of the DHCR7/NADSYN1 locus and the CYP2R1 gene might be related to the inefficient utilization of vitamin D independent from vitamin D levels, and it might result in differences in the clinical features of PD patients.

Classical complement pathway factor alterations in narcolepsy.

OBJECTIVE: Narcolepsy is a chronic sleep disorder long hypothesised to be an autoimmune disease. Complement-mediated immune mechanisms have not been investigated in detail in narcolepsy. Our aim was to establish the significance of classical pathway activation in narcolepsy. METHODS: Sera of 42 narcolepsy patients and 26 healthy controls were screened with ELISA to determine the levels of C1q, C3a, C4d and complement component 4 binding protein (C4BP). A home-made ELISA method was developed to detect antibodies to C4BP-alpha (anti-C4BPA). The correlation between complement levels and clinical findings was examined. RESULTS: C1q levels were significantly higher in narcolepsy patients while C4d and C4BP levels were significantly lower compared to healthy controls. C3a levels were comparable among patients and controls. Eleven narcolepsy patients showed serum anti-C4BPA levels. Total rapid eye movements (REM) time, sleep onset latency, REM sleep latency, sleep activity, percentage of wakefulness after sleep onset and Epworth sleepiness scale scores were correlated with levels of different complement factors. CONCLUSION: Complement-mediated immune mechanisms might partake in narcolepsy pathogenesis. The precise role of autoantibodies on complement level alterations needs to be investigated. Levels of complement factors and degradation products may potentially be utilised as biomarkers to predict the clinical severity of narcolepsy.

An Exploratory Study of Cognitive Involvement in Hereditary Transthyretin Amyloidosis.

OBJECTIVES: Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is an autosomal dominant disorder caused by mutations of the transthyretin (TTR) gene. The mutant ATTRv protein causes a systemic accumulation of amyloid fibrils in various organs. TTR is an important protein in the central nervous system physiology for the maintenance of normal cognitive process during aging, amidated neuropeptide processing, and nerve regeneration. The neuroprotective effect of transthyretin has been widely documented in animal models. Cognitive consequences of the mutant TTR in hereditary ATTRv amyloidosis patients remain still to be elucidated. We designed this study to investigate the cognitive involvement in ATTRv amyloidosis. METHODS: Detailed neuropsychological tests and cranial MRIs were performed. Biomarkers including amyloid beta 1-42, total tau, and phosphorylated tau were investigated in the cerebrospinal fluid samples. RESULTS: Median age of the cohort was 52 years (ranges 34-72). Neuropsychological assessment results were compatible with impaired executive functions (in all patients except one with only bilateral carpal tunnel syndrome, long-term visual and long-term verbal memory (severe in four patients and moderate in one). Visuospatial judgment and perception were impaired in six. Mean cerebrospinal fluid Aß1-42 (pg/ml) was 878.0 ± 249.5 in patients with cortical atrophyin MRI whereas 1210.0 ± 45.9 in patients without any cortical atrophy. Cranial MRI showed cortical atrophy in six patients (6/10). CONCLUSION: Our data showed the significance of the TTR protein in cognitive functions and highlighted the importance of the close follow-up of cognitive functions in ATTRv amyloidosis patients.

Serum glial fibrillary acidic protein (GFAP)-antibody in idiopathic intracranial hypertension.

AIM: Idiopathic intracranial hypertension (IIH), a disease of obscure origin, is characterized by headache and visual disturbances due to increased intracranial pressure. Recent line of evidence has suggested involvement of inflammation in IIH pathogenesis thus bringing forward anti-glial autoimmunity as a potential contributor of IIH. Glial fibrillary acidic protein (GFAP) is a major astrocytic autoantigen associated with a specific form of meningoencephalitis. MATERIALS AND METHODS: In this study, we investigated the presence of GFAP-antibody in 65 sera (49 obtained during active disease and 16 during remission) and in 15 cerebrospinal fluid (CSF) samples of 58 consecutively recruited IIH patients using cell based assay and indirect immunohistochemistry. RESULTS: GFAP-antibody was found in active period sera of 2 IIH patients with classical symptoms and good treatment response. Two remission period sera obtained at different time points from one of these cases showed lower titers of GFAP-antibody positivity. IgG from positive samples yielded an astrocytic immunoreactivity pattern. None of the CSF samples showed GFAP-antibodies. CONCLUSIONS: These results suggest that anti-astrocyte autoimmunity might be present in a fraction of IIH patients. Exact pathogenic significance of this association needs to be further studied.

Intracranial hypertension related to cerebral venous thrombosis; and acute ischemic stroke with micro-infarcts associated with IgG4-related disease.

IgG4-related systemic disease (IgG4-RD) is characterized by an inflammatory reaction rich in IgG4-positive plasma cells, affecting multiple organs. This report describes a case who was diagnosed with IgG4-RD, having cerebral venous thrombosis and a subsequent acute ischemic stroke of undetermined cause. A 47-year-old woman presented with headache, visual disturbance and eyelid swelling and two years later she was admitted with acute attacks of mild left lower limb sensory-motor monoparesis. Indirect immunohistochemistry assay showed elevated level of IgG4, labeling neurons of the central nervous system, suggesting an immunological process possibly affecting vascular structures. Our experience suggests that IgG4-RD may be considered in patients with ischemic stroke and cerebral venous system involvement.

Glial and neuronal antibodies in patients with idiopathic intracranial hypertension.

Headache and visual disturbances are the main presenting symptoms of idiopathic intracranial hypertension (IIH) characterized by increased intracranial pressure (ICP) with an unknown cause. We aimed to investigate the antibodies against optic neuritis-associated glial antigens, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) and uncharacterized neuronal membrane antigens in IIH patients. Consecutive patients diagnosed according to Friedman revised diagnostic criteria and control subjects were included after their consent. All serum samples were analyzed for antibodies against AQP4 and MOG using cell-based immunofluorescent assays and for uncharacterized neuronal membrane antigens by indirect immunocytochemistry utilizing live neurons. Sera of 34 patients with IIH and 40 control subjects were investigated but none of the patients showed AQP4 and MOG antibodies. However, serum IgG of five IIH patients showed reactivity against membrane antigens of rat hippocampal and cortical neurons. Interestingly, three out of these five patients had nonspecific white matter lesions on MRI, whereas only four of all other patients had these lesions (p = 0.048). AQP4 and MOG antibodies do not seem to have a role in the pathophysiology of IIH. However, association of immunocytochemistry findings with the presence of white matter lesions may suggest that immunological factors contribute to the pathogenesis of IIH in at least some of the patients.

The Association Between Clusterin and APOE Polymorphisms and Late-Onset Alzheimer Disease in a Turkish Cohort.

Previous studies have demonstrated that clusterin (CLU), which is also known as apolipoprotein J, is involved in the pathogenesis of Alzheimer disease (AD). In this study, we investigated the association between rs2279590, rs11136000, and rs9331888 single-nucleotide polymorphisms (SNPs) in CLU and apolipoprotein E (APOE) genotypes in a cohort of Turkish patients with late-onset AD (LOAD). There were 183 patients with LOAD and 154 healthy controls included in the study. The CLU and APOE polymorphisms were genotyped using the LightSNiP assay. The "GG" genotype of rs9331888 was significantly more frequent in patients with LOAD. The "CC" genotype of the SNP was significantly more frequent in controls. The rs9331888 "GG" genotype in patients and the "CC" genotype in controls were significantly higher in non-∊4 allele carriers of APOE The haplotype analysis showed the CLU "GCG" haplotype was a risk haplotype. Our findings indicate the rs9331888 SNP of CLU is associated with LOAD independent of APOE.

Vitamin D deficiency might pose a greater risk for ApoEɛ4 non-carrier Alzheimer's disease patients.

Vitamin D is a secosteroid hormone that shares a synthetic pathway with cholesterol. ApoE, which is involved in the transport of cholesterol, is the most significant genetic risk factor for sporadic Alzheimer's disease (AD). Surprisingly, recent studies have indicated the presence of an evolutionary juncture between these two molecules. To demonstrate this possible relationship, we investigated serum levels of 25-hydroxyvitamin-D3 (25OHD) in patients with early onset-AD (EOAD; n:22), late onset-AD (LOAD; n:72), mild cognitive impairment (MCI; n:32) and in healthy subjects (n:70). We then analyzed the correlation between 25OHD and cytokines, BDNF and Hsp90 with respect to ApoE alleles, as these molecules were investigated in our previous studies. The LOAD patients had low levels of 25OHD, but these low levels originated only from ApoEɛ4 non-carrier patients. Negative correlations were observed between serum 25OHD and TNFα, IL-1ß or IL-6 levels in healthy subjects or MCI patients, but these same correlations were positive in LOAD patients. ApoE alleles indicated that these positive correlations exist only in ɛ4 carrier LOAD patients. Consequently, our results indicate that vitamin D deficiency presents a greater risk for ApoEɛ4 non-carrier AD patients than for ɛ4 carriers. Therefore, it might be beneficial to monitor the vitamin D status of ApoEɛ4 allele non-carrier AD patients.

Efficiency of the Vitamin D Status Diagnosticator amongst Geriatric Patients with COVID-19.

The vitamin D status diagnosticator (VDSD), a 16-item tool, effectively identifies hypovitaminosis D in healthy older adults and can assist in determining the need for blood tests in this population. Assessing vitamin D levels is particularly crucial in the context of COVID-19. This study aimed to evaluate the VDSD's effectiveness in pinpointing hypovitaminosis D in older adults affected by COVID-19. The research involved 102 unsupplemented geriatric inpatients consecutively admitted to the acute geriatric division of Angers University Hospital, France, with an average age of 85.0 ± 5.9 years (47.1% women). The physician-administered VDSD was conducted simultaneously with the measurement of serum 25-hydroxyvitamin D (25(OH)D). Hypovitaminosis D was defined as a serum 25(OH)D concentration of ≤75 nmol/L for vitamin D insufficiency and ≤50 nmol/L for vitamin D deficiency. Results revealed that 87 participants (85.3%) had vitamin D insufficiency and 63 (61.8%) had vitamin D deficiency. The VDSD accurately identified vitamin D deficiency with an area under the curve (AUC) of 0.81 and an odds ratio (OR) of 40. However, its accuracy in identifying vitamin D insufficiency was lower (AUC = 0.57). In conclusion, the 16-item VDSD, a concise questionnaire, effectively identifies vitamin D deficiency in geriatric patients with COVID-19. This tool can be valuable in guiding the decision to administer vitamin D supplementation during the early stages of COVID-19.

Fibrillar Alpha-Synuclein Alters the Intracellular Chaperone Levels within Hours of Its Internalization.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. According to the Braak hypothesis, the disease spreads along specific neuroanatomical pathways. Studies indicate that fibrillar alpha-synuclein (F-αSyn) can propagate from cell-to-cell by following intercellular connections, leading to the selective death of certain cell groups like substantia nigra dopaminergic neurons and advancing the pathology. Internalized F-αSyn can be eliminated by lysosomes, proteasomes, or chaperones before it replicates inside the cell. Research has shown that F-αSyn can somehow escape from endosomes, lysosomes, and proteasomes and replicate itself. However, the impact of chaperones on intracellular levels during the initial hours of their internalization remains unknown. The present study investigates the effect of F-αSyn on chaperone levels within the first 6 and 12 h after internalization. Our findings showed that within the first 6 h, Hsc70 and Hsp90 levels were increased, while within 12 h, F-αSyn leads to a decrease or suppression of numerous intracellular chaperone levels. Exploring the pathological effects of PD on cells will contribute to identifying more targets for therapeutic interventions.

Vitamin D and behavioral disorders in older adults: results from the CLIP study.

OBJECTIVES: Vitamin D is involved in brain health and function. Our objective was to determine whether vitamin D deficiency was associated with behavioral disorders in geriatric patients. DESIGN: The observational cross-sectional CLIP (Cognition and LIPophilic vitamins) study. The report followed the STROBE statement. SETTING: Geriatric acute care unit in a tertiary university hospital in France for 3 months at the end of winter and beginning of spring. PARTICIPANTS: 272 patients ≥65 years consecutively hospitalized or seen in consultation. MEASUREMENTS: Participants were separated into two groups according to vitamin D deficiency (i.e., serum 25-hydroxyvitamin D ≤25 nmol/L). Behavior was assessed using the reduced version of the Neuropsychiatric Inventory Scale (NPI-R) score and subscores. Age, sex, BMI, education level, comorbidities, MMSE and GDS scores, use psychoactive drugs and vitamin D supplements, and serum concentrations of calcium, parathyroid hormone, TSH and estimated glomerular filtration rate (eGFR) were used as potential confounders. RESULTS: Participants with vitamin D deficiency (n = 78) had similar NPI-R score (17.4 ± 20.3 versus 17.2 ± 16.1, p = 0.92) but higher (i.e., worse) subscore of agitation and aggressiveness (2.0 ± 3.3 versus 1.2 ± 2.4, p = 0.02) and higher (i.e., worse) subscore of disinhibition (0.99 ± 2.98 versus 0.38 ± 1.42, p = 0.02) than those without vitamin D deficiency (n = 194). In multiple linear regressions, vitamin D deficiency was inversely associated with the subscore of agitation and aggressiveness (ß = 1.37, p = 0.005) and with the subscore of disinhibition (ß = 0.96, p = 0.008). CONCLUSION: Vitamin D deficiency was associated with more severe subscores of agitation and aggressiveness and of disinhibition among older adults. This provides a scientific basis to test the efficacy of vitamin D supplementation on behavioral disorders in older patients with vitamin D deficiency.

Beta amyloid suppresses the expression of the vitamin d receptor gene and induces the expression of the vitamin d catabolic enzyme gene in hippocampal neurons.

BACKGROUND/AIMS: The beta amyloid aggregations present in Alzheimer's disease affect neurons through various toxic alterations. The aim of this study was to determine the expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D3 24-hydroxylase (an accelerator of vitamin D catabolism), and the L-type voltage-sensitive calcium channel A1C (LVSCC-A1C) in hippocampal neurons in response to beta amyloid and vitamin D treatments to test the protective effects of vitamin D and the probable effects of beta amyloid on vitamin D catabolism. METHODS: The expression of the VDR, 24-hydroxylase (24OHase) and LVSCC-A1C mRNAs were studied using quantitative real-time polymerase chain reaction, and the cytotoxicity levels were determined by an ELISA in primary hippocampal neuron cultures prepared from Sprague-Dawley rat embryos. RESULTS: Our results demonstrated that beta amyloid suppressed the expression of VDR mRNA and induced the expression of 24OHase and LVSCC-A1C mRNAs. CONCLUSION: Beta amyloid may disrupt the vitamin D-VDR pathway and cause defective utilization of vitamin D by suppressing the level of the VDR and elevating the level of 24OHase.

Vitamin D inquiry in hippocampal neurons: consequences of vitamin D-VDR pathway disruption on calcium channel and the vitamin D requirement.

Vitamin D receptor (VDR) and the enzymes involved in bioactivation of vitamin D, shown to be expressed in the central nervous system, particularly in areas affected by neurodegenerative disorders, especially in hippocampus. We showed that amyloid beta (Aß) pathology includes VDR protein depletion and vitamin D-VDR pathway disruption either induced by Aß or by VDR siRNA have very similar effects on cortical neurons. The goal of this study is to show the presence of 25 hydroxy vitamin D3-24 hydroxylase (24OHase) which is essential for vitamin D catabolism in hippocampal and cortical neurons. Additional goal is to compare the expression pattern of VDR and 24OHase both in hippocampal and in cortical neurons and to investigate the effects of VDR suppression in hippocampal neurons in order to see whether similar mechanisms work in hippocampus and cerebral cortex. Primary neuronal cultures were prepared from Sprague-dawley rat embryos. qRT-PCR was performed to determine VDR, 24OHase, and LVSCC-A1C mRNA expression levels. Cytotoxicity levels were determined by ELISA. Our findings illustrate that 24OHase mRNA was present both in hippocampal and in cortical neurons. VDR and 24OHase mRNA were higher in hippocampal neurons than the cortical ones. LVSCC-A1C mRNA levels increased in hippocampal neurons when VDR is down-regulated. Our results indicate that hippocampal neurons response to VDR suppression similar as cortical neurons, regarding calcium channel regulation. Higher gene expression of 24OHase and VDR might indicate "higher requirement of vitamin D" in hippocampus and potential consequences of vitamin D deficiency in cognitive decline, neurodegeneration, and Alzheimer's disease.

Vitamin D, a Secosteroid Hormone and Its Multifunctional Receptor, Vitamin D Receptor, in Alzheimer's Type Neurodegeneration.

Vitamin D is a secosteroid hormone exerting neurosteroid-like properties. Its well-known nuclear hormone receptor, and recently proposed as a mitochondrial transcription factor, vitamin D receptor, acts for its primary functions. The second receptor is an endoplasmic reticulum protein, protein disulfide isomerase A3 (PDIA3), suggested to act as a rapid response. Vitamin D has effects on various systems, particularly through calcium metabolism. Among them, the nervous system has an important place in the context of our subject. Recent studies have shown that vitamin D and its receptors have numerous effects on the nervous system. Neurodegeneration is a long-term process. Throughout a human life span, so is vitamin D deficiency. Our previous studies and others have suggested that the out-come of long-term vitamin D deficiency (hypovitaminosis D or inefficient utilization of vitamin D), may lead neurons to be vulnerable to aging and neurodegeneration. We suggest that keeping vitamin D levels at adequate levels at all stages of life, considering new approaches such as agonists that can activate vitamin D receptors, and utilizing other derivatives produced in the synthesis process with UVB are crucial when considering vitamin D-based intervention studies. Given most aspects of vitamin D, this review outlines how vitamin D and its receptors work and are involved in neurodegeneration, emphasizing Alzheimer's disease.

Amyloid ß,α-Synuclein and Amyloid ß-α-Synuclein Combination Exert Significant but Different Alterations in Inflammatory Response Profile in Differentiated Human SH-SY5Y Cells.

Neurodegeneration is a condition in which the neuronal structure and functions are altered with reduced neuronal survival and increased neuronal death in the central nervous system (CNS). Amyloid-ß (Aß) is the pathological hallmark of a common neurodegenerative disorder, Alzheimer disease. Parkinson disease and dementia with Lewy bodies are among α-synucleinopathies characterized by abnormal accumulation of insoluble α-synuclein protein. Neuroinflammation is seen in those neurodegenerative disorders regulated by cytokines and chemokines released from neurons, microglia, and astrocytes. Our study aimed to (1) define steady-state levels of cytokines and immune response modulators in SH-SY5Y cells that were differentiated into neuron-like cells and (2) compare the levels of target cytokines in cellular models of neurodegenerative disorders, namely, AD, PD, and DLB-like pathologies. AD, PD, and DLB-like pathologies were established by 6 µM Aß1-42 administration, SNCA (α-synuclein) overexpression, and SNCA overexpression was followed by Aß1-42 treatment, respectively. Alterations in the levels of 40 released inflammatory proteins (IPs) were analyzed by chemiluminescence-based Western/dot blot. Overexpression of human α-synuclein and administration of Aß1-42 significantly changed the profile of IPs secretion, with particularly significant changes in CSF2, CCL5, CXCL8, CXCL10, ICAM1, IL1B, and IL16. Bioinformatics analysis revealed possible interactions between α-synuclein and IL1B. While TGF1, CCL2, TNF, IL10, IL4, and IL1B IPs were associated with Aß 1-42, Aß 1-42 treatment together with α-synuclein, overexpression is associated only with the IL6 protein. Consequently, AD, PD, and DLB-like pathologies might exert significant but different alterations in the inflammatory response.

Chloride intracellular channel protein-1 (CLIC1) antibody in multiple sclerosis patients with predominant optic nerve and spinal cord involvement.

INTRODUCTION: Antibodies to cell surface proteins of astrocytes have been described in chronic inflammatory demyelinating disorders (CIDD) of the central nervous system including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Our aim was to identify novel anti-astrocyte autoantibodies in relapsing remitting MS (RRMS) patients presenting predominantly with spinal cord and optic nerve attacks (MS-SCON). METHODS: Sera of 29 MS-SCON patients and 36 healthy controls were screened with indirect immunofluorescence to identify IgG reacting with human astrocyte cultures. Putative target autoantigens were investigated with immunoprecipitation (IP) and liquid chromatography-mass/mass spectrometry (LC-MS/MS) studies using cultured human astrocytes. Validation of LC-MS/MS results was carried out by IP and ELISA. RESULTS: Antibodies to astrocytic cell surface antigens were detected in 5 MS-SCON patients by immunocytochemistry. LC-MS/MS analysis identified chloride intracellular channel protein-1 (CLIC1) as the single common membrane antigen in 2 patients with MS-SCON. IP experiments performed with the commercial CLIC1 antibody confirmed CLIC1-antibody. Home made ELISA using recombinant CLIC1 protein as the target antigen identified CLIC1 antibodies in 9/29 MS-SCON and 3/15 relapsing inflammatory optic neuritis (RION) patients but in none of the 30 NMOSD patients, 36 RRMS patients with only one or no myelitis/optic neuritis attacks and 36 healthy controls. Patients with CLIC1-antibodies showed trends towards exhibiting reduced disability scores. CONCLUSION: CLIC1-antibody was identified for the first time in MS and RION patients, confirming once again anti-astrocytic autoimmunity in CIDD. CLIC1-antibody may potentially be utilized as a diagnostic biomarker for differentiation of MS from NMOSD.

Vitamin D receptor regulates transcription of mitochondrial DNA and directly interacts with mitochondrial DNA and TFAM.

Vitamin D receptor (VDR) is an essential transcription factor (TF) synthesized in different cell types. We hypothesized that VDR might also act as a mitochondrial TF. We conducted the experiments in primary cortical neurons, PC12, HEK293T, SH-SY5Y cell lines, human peripheral blood mononuclear cells (PBMC) and human brain. We showed that vitamin D/VDR affects the expression of mitochondrial DNA (mtDNA) encoded oxidative phosphorylation (OXPHOS) subunits. We observed the co-localization of VDR with mitochondria and the mtDNA with confocal microscopy. mtDNA-chromatin-immunoprecipitation and electrophoretic mobility shift assays indicated that VDR was able to bind to the mtDNA D-loop site in several locations, with a consensus sequence "MMHKCA." We also reported the possible interaction between VDR and mitochondrial transcription factor A (TFAM) and their binding sites located in close proximity in mtDNA. Consequently, our results showed for the first time that VDR was able to bind and regulate mtDNA transcription and interact with TFAM even in the human brain. These results not only revealed a novel function of VDR, but also showed that VDR is indispensable for energy demanded cells.

Vitamin D receptor gene haplotype is associated with late-onset Alzheimer's disease.

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.

Could Amyloid-ß 1-42 or α-Synuclein Interact Directly with Mitochondrial DNA? A Hypothesis.

The amyloid ß (Aß) and the α-synuclein (α-syn) are shown to be translocated into mitochondria. Even though their roles are widely investigated in pathological conditions, information on the presence and functions of Aß and α-syn in mitochondria in endogenous levels is somewhat limited. We hypothesized that endogenous Aß fragments or α-syn could interact with mitochondrial DNA (mtDNA) directly or influence RNAs or transcription factors in mitochondria and change the mtDNA transcription profile. In this review, we summarized clues of these possible interactions.

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health.

Vitamin D3 has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world's population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.