Esin Candas

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-1β 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.

Vitamin D Receptor Regulates Amyloid Beta 1–42 Production with Protein Disulfide Isomerase A3

The challenge of understanding the biology of neuronal amyloid processing could provide a basis for understanding the amyloid pathology in Alzheimers disease (AD). Based on our previous studies, we have suggested that AD might be the consequence of a hormonal imbalance in which the critical hormone is vitamin D. The present study primarily focused on the creation of a condition that prevents the genomic or nongenomic action of vitamin D by disrupting vitamin D receptors (VDR or PDIA3/1,25MARRS); the effects of these disruptions on the series of proteins involved in secretases that play a crucial role in amyloid pathology and on amyloid beta (Aβ) production in primary cortical neurons were observed. VDR and PDIA3/1,25MARRS genes were silenced separately or simultaneously in E16 primary rat cortical neurons. The expression of target genes involved in APP processing, including Presenilin1, Presenilin2, Nicastrin, BACE1, ADAM10, and APP, was investigated with qRT-PCR and Western blot in this model. 1,25-Dihydroxyvitamin D3 treatments were used to verify any transcriptional regulation data gathered from siRNA treatments by determining the mRNA expression of the target genes. Immunofluorescence labeling was used for the verification of silencing experiments and intracellular Aβ1-42 production. Extracellular Aβ1-42 level was assessed with ELISA. mRNA and protein expression results showed that 1,25-dihydroxyvitamin D3 might affect the transcriptional regulation of the genes involved in APP processing. The intracellular and extracellular Aβ1-42 measurements in our study support this suggestion. Consequently, we suggest that 1,25-dihydroxyvitamin D3 and its receptors are important parts of the amyloid processing pathway in neurons.

The Transcriptional Regulatory Properties of Amyloid Beta 1–42 may Include Regulation of Genes Related to Neurodegeneration

Our previous study demonstrated the translocation of Aβ1–42 to the nucleus in response to antibiotic treatment, and interpreted it as a possible transcriptional response of Aβ1–42 to antibiotics. The present study aims to investigate how amyloid acts on the key elements of neurodegeneration and the molecules involved in the induction of Aβ1–42 production. For this purpose, we investigated the acute effect of Aβ1–42 on the transcriptional levels of genes that have roles in the mechanisms that produce Aβ itself: alpha secretase (ADAM10), beta secretase (BACE1), the gamma secretase complex (PS-1, PS-2, Nicastrin), the substrate APP, APOE (the significant risk factor for sporadic form of the AD), TREM2 (recently indicated as a contributor to AD risk), NMDAR subunits and PKCzeta (contributors of memory and learning), and key elements of tau pathology such as tau, GSK3α, GSK3β, and Cdk5. Additionally, we examined cholecalciferol metabolism-related enzyme 1α-hydroxylase (1αOHase) in primary cortical neurons with qRT-PCR. Our results indicate that Aβ1–42 has an effect on most of the target genes. This effect involves regulation of the amyloidogenic pathway in a complex manner, specifically, a general downregulation in NMDARs, ApoE, Trem2, and 1αOHase genes, and general up-regulation of tau pathway-related genes. We speculate that the presence of Aβ impacts the neurons not only with toxic events but also at the transcriptional level. The nuclear localization of Aβ1–42 and its regulatory effects on the target genes that we investigated in present study indicates Aβ1–42 as a transcriptional regulator of genes related to neurodegeneration.

The role of astaxanthin on transcriptional regulation of NMDA receptors, voltage sensitive calcium channels and calcium binding proteins in primary cortical neurons

Introduction Calcium (Ca) is the phenomenon intracellular molecule that regulate many cellular process in neurons physiologically. Calcium dysregulation may occur in neurons due to excessive synaptic release of glutamate or other reasons related with neurodegeneration. Astaxanthin is a carotenoid that has antioxidant effect in cell. The purpose of this study was to investigate whether astaxanthin affects NMDA subunits, calcium binding proteins and L Type voltage sensitive Ca-channels (LVSCC) in primary cortical neuron cultures in order to see its role in calcium metabolism. Methods Primary cortical neurons were prepared from embryonic day 16-Sprague Dawley rat embryos. The cultures were treated with 10 nM and 20 nM astaxanthin on day 7. NMDA subunits, LVSCC-A1C and LVSCC-A1D, calbindinD28k and parvalbumin mRNA expression levels was determined by qRT-PCR at 4, 24 and 48 hours. Results Our findings indicate that astaxanthin could have direct or indirect outcome on calcium homeostasis by regulating mRNA expression levels of NMDA subunits, LVSCC-A1C and LVSCC-A1D, calbindinD28k and parvalbumin by a dose and time dependent manner. Conclusion Neuroprotective effects of astaxanthin as a Ca homeostasis regulator should be noted throughout neurodegenerative disorders, and neurosurgery applications.

ASSOCIATION BETWEEN NADSYN1/DHCR7 AND CYP2R1 GENOTYPES AND PARKINSON’S DISEASE AND ITS CLINICAL FEATURES

dysfunction, however, the association between MT genetic variants and AD has not been fully explored in large datasets. Methods:The Alzheimer’s Disease Genetics Consortium (ADGC) recently genotyped 8,706 AD cases and 7,002 healthy controls of European ancestry from five cohorts using the Illumina Exome-Chip 1.0 containing 227MT single nucleotide variants (SNVs). Each cohort was analyzed separately for variants with minor allele count (MAC) 10 and call rate 0.95 (94 variants on average). In gene-based tests, only SNVs with minor allele frequency (MAF) <0.05 were considered, and genes with 2 SNVs and cumulative MAC 10 were tested. Associations with AD status were tested using single variant SCORE tests and gene-based (SKAT-O) tests in seqMeta in R package, controlling for age, sex, and principal components of ancestry. Results were combined across cohorts using meta-analysis. Bonferroni-corrected thresholds were used to determine statistical significance for single variant (a1⁄48.6310) and gene-based (a1⁄44.5310) associations. Finally, SNVs (MAF<0.05) in genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes were aggregated for testing association with AD. Results: In single variant analyses, one missense SNV in MT-ND3which encodes NADH dehydrogenase 3 involved in oxidative phosphorylation of ATP (rs2853826, Thr114Ala, MAF1⁄40.22) was significantly associated with AD risk (OR1⁄41.043; P1⁄42.50310). The most significant gene-based association finding was obtained withMT-TP (P1⁄4 7.9310), but this result did not survive correction for multiple testing. However, the hypothesis-driven test of aggregated rare variants in the OXPHOS complex was significant (P1⁄40.02, cumulative MAF1⁄40.015), which is consistent with previous reports that the expression level of OXPHOS genes is significantly lower in AD than in MCI or cognitively healthy subjects. Conclusions:We identified significant association of AD risk with one common MT SNV and the collective group of OXPHOS pathway genes. A replication study of independent cohorts from the International Genomics of Alzheimer’s Project is currently underway. Additional replication and discovery of novel rare AD-associated MT variants in datasets from the Alzheimer’s Disease Sequencing Project data are also in progress.

Erratum to: GC and VDR SNPs and Vitamin D Levels in Parkinson's Disease: The Relevance to Clinical Features.

Tables 3, 4 and supplementary Table 4 of the original article contained errors in the labeling of the genotype and allele columns for the first GC SNP (rs2282679). The correct labels for the genotype columns (left to right) are ‘AA’, ‘CA’ and ‘CC’. The correct labels for the allele columns (left to right) are ‘A’ and ‘C’. The error did not affect the genotype or allele distributions, statistical analysis or results, and thus the conclusions of the study were not affected. The authors regret the inconvenience caused to the readers. ThecorrectedTables 3, 4 and supplementary Table 4 are given along with this erratum.

VDR SUPPRESSION AND CYP24 INDUCTION BY AMYLOID BETA MIGHT INVOLVE MIR-27B-3P, LET-7A-5P, MIR-125B-5P IN AMYLOID BETA-TREATED CORTICAL NEURON CULTURES

period, 3-hour restraint stress, and 12-hour post stress period. To evaluate the effects of blocking the transactivation arm of GR signaling through GR dimerization, we crossed APP/PS1 mice with the glucocorticoid receptor dimerization deficient mouse model (GRdim), to create GRdim APP mice. We also studied the effects of pharmacologically blockingGR dimerization using Compound A, administered via reverse microdialysis before restraint stress. Results:We observed a significant difference between male and female mice in the percent increase in ISF Ab during acute stress, with female mice having a much greater and sustained increase in ISF Ab compared to males. ISF Ab levels in female GRdim APP mice did not rise dramatically during acute stress, and stayed near baseline during the post stress period. Compound A completely blocked the increase in ISF Ab induced by restraint stress in female mice. Conclusions: These results suggest that females are more sensitive to stress-induced increases in Ab, and that acute stress increases Ab in female mice through a GR dimerization dependent mechanism.