Alterations in T-Cell Transcription Factors and Cytokine Gene Expression in Late-Onset Alzheimer’s Disease

2021 ◽  
pp. 1-21
Author(s):  
Masoud Neshan ◽  
Seyed Kazem Malakouti ◽  
Leila Kamalzadeh ◽  
Mina Makvand ◽  
Arezoo Campbell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transcription Factors ◽  
T Cell ◽  
Late Onset ◽  
Cytokine Gene Expression ◽  
Mrna Levels ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ

Background: Late-onset Alzheimer’s disease (LOAD) is associated with many environmental and genetic factors. The effect of systemic inflammation on the pathogenesis of neurodegenerative diseases such as AD has been strongly suggested. T helper cells (Th) are one of the important components of the immune system and can easily infiltrate the brain in pathological conditions. The development of each Th-subset depends on the production of unique cytokines and their main regulator. Objective: This study aimed to compare the mRNA levels of Th-related genes derived from peripheral blood mononuclear cells of LOAD patients with control. Also, the identification of the most important Th1/Th2 genes and downstream pathways that may be involved in the pathogenesis of AD was followed by computational approaches. Methods: This study invloved 30 patients with LOAD and 30 non-demented controls. The relative expression of T-cell cytokines (IFN-γ, TNF-α, IL-4, and IL-5) and transcription factors (T-bet and GATA-3) were assessed using real-time PCR. Additionally, protein-protein interaction (PPI) was investigated by gene network construction. Results: A significant decrease at T-bet, IFN-γ, TNF-α, and GATA-3 mRNA levels was detected in the LOAD group, compared to the controls. However, there was no significant difference in IL-4 or IL-5 mRNA levels. Network analysis revealed a list of the highly connected protein (hubs) related to mitogen-activated protein kinase (MAPK) signaling and Th17 cell differentiation pathways. Conclusion: The findings point to a molecular dysregulation in Th-related genes, which can promising in the early diagnosis or targeted interventions of AD. Furthermore, the PPI analysis showed that upstream off-target stimulation may involve MAPK cascade activation and Th17 axis induction.

scholarly journals C-338A Polymorphism of the Endothelin-Converting Enzyme (ECE-1) Gene and the Susceptibility to Sporadic Late-Onset Alzheimer’s Disease and Coronary Artery Disease

2008 ◽  
Vol 24 (3) ◽  
pp. 175-179 ◽  
Author(s):  
Renato Scacchi ◽  
Giuseppe Gambina ◽  
Elisabetta Broggio ◽  
Maria Ruggeri ◽  
Rosa Maria Corbo
Keyword(s):  
Alzheimer’S Disease ◽  
Coronary Artery Disease ◽  
Alzheimer's Disease ◽  
Coronary Artery ◽  
Late Onset ◽  
Protective Role ◽  
Converting Enzyme ◽  
Significant Difference ◽  
Endothelin Converting Enzyme ◽  
Artery Disease

The human endothelin-converting enzyme (ECE) is involved inβ-amyloid synthesis and regulation of the endothelin-1 (ET-1) vasoconstricting peptide. We investigated the distribution of the C-338A polymorphism of the ECE-1b gene in sporadic late-onset Alzheimer’s disease (LOAD) and in coronary artery disease (CAD) to verify its role in the onset of these two complex diseases. Two cohorts of 458 Italian Caucasian LOAD patients and 165 CAD patients were examined for the C-338A polymorphism and compared with respective control samples (260 and 106 subjects, respectively). The A allele was less present in LOAD patients than in controls, but an at limits statistically significant difference was achieved only in subjects aged less than 80 years, where only the AA genotypes appeared to have a protective role against the onset of the sporadic LOAD. For the overall CAD sample the pattern was similar and significant differences were observed only in subjects non carrying the apolipoprotein E (APOE) e*4 allele, where the A allele carrying genotypes had a protective role against the onset of the disease.

Transcription Factor BACH2 Inhibits AP1 Proteins JunB and FosL1 in Umbilical Cord Blood (UCB) CD4+ T-Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1743-1743
Author(s):  
Mathew L. Lesniewski ◽  
Laura R. Fanning ◽  
Margeret Kozik ◽  
Richard P. Weitzel ◽  
Yeal Hegerfeldt ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cd4 T Cells ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Tnf Α ◽  
Ifn Γ ◽  
Sirna Knockdown

Abstract Introduction: Umbilical cord blood (UCB) CD4+ T-cells have been shown to express significant levels of BACH2 transcription factor protein compared to adult blood (AB) CD4+ T-cells. Previously, NFAT1 siRNA knockdown of UCB T-cells exhibited a significantly higher BACH2 mRNA expression, and IFN-γ, TNF-α. and CTLA-4 mRNA levels were significantly suppressed. BACH2, a member of the b-Zip family, has been shown to act as a heterodimer with the bZip protein MafK, as a transcriptional inhibitor via recruitment of a histone deacetylase class II complex (HDAC II) in differentiating B-cells, and neurons. Due to observed inverse expression of BACH2 and NFAT1 in UCB CD4+ T-cells, we hypothesized that BACH2 may regulate transcription factors known to bind with NFAT1 including AP-1 proteins JunB and FosL1. We tested this by siRNA knockdown of BACH2 in primary UCB-derived CD4+ T-cells. Key developmental transcription factors JUNB, FosL1, NFAT1 and downstream IFN-γ, and TNF-α were mRNA analyzed. Methods: UCB T-cells were purified using autoMACs system (Miltenyi). After overnight culture, T-cells were transfected with BACH2 siRNA (Dharmacon) using Amaxa Nucleofector system (Amaxa Inc). Both siRNA treated and control cells were incubated in media for 18 hours, and then stimulated using anti-CD3/anti-CD28 antibodies (BD BioScience). Aliquots of cells were collected at specified time points post-stimulation for protein and total RNA isolation. The relative change in mRNA levels for BACH2, JUNB, FosL1, IFN-γ, NFAT1, and TNF-α were determined by Lightcycler SybrGreen real time RT-PCR system (Roche). siRNA knockdown of BACH2 protein in transfected UCB T-cells was confirmed by western blot. Results: Real-time RT-PCR of BACH2 siRNA treated UCB CD4+ T-cells stimulated with anti-CD3/CD28 antibodies and analyzed after 6 hrs of stimulation showed a 4 log increase in FosL1 and NFAT1 mRNA, a 3 log increase in JunB mRNA, a 5 log increase in IFN-γ as compared to stimulated control UCB T-cells. TNF-α mRNA was decreased by 5 logs in BACH2 siRNA treated UCB T-cells as compared to control. CD3/CD28 stimulated untransfected UCB T-cells were previously shown to have decrease expression of NFAT1, JunB, FosL1, IFN-γ, and TNF-α, and in UCB T-cells compared to stimulated AB T-cells. Conclusions: BACH2 expression correlates with an inhibition of expression of AP1 transcription regulatory proteins in UCB T-cells during primary CD3/CD28 stimulation. The complete activation of the T-cell requires the activation of AP1 by CD28 pathway otherwise the antigen presenting cell signals the T-cell to enter anergy. In UCB CD4+ T-cells express BACH2, which acts as a transcriptional inhibitor of two critical AP1 genes, JUNB and FosL1, which mediate the CD28 co-stimulatory pathway. These results further suggests that expression of BACH2 in UCB T-cells may contribute to lower incidence of alloreactivity observed in leukemia patients receiving UCB stem cells compared to AB bone marrow stem cells and thus leads to low GVHD, and contribute to the weak Th1 response seen in stimulated UCB T-cells by reduced amounts of AP1 protein available for activating the T-cell.

O2-06-06: SNPS in MAPT are associated with cerebrospinal fluid Tau levels, MAPT mRNA levels, and age at onset of late-onset Alzheimer's disease

2008 ◽  
Vol 4 ◽  
pp. T145-T145
Author(s):  
John S.K. Kauwe ◽  
Carlos Cruchaga ◽  
Kevin Mayo ◽  
Chiara Fenoglio ◽  
Sarah Bertelsen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Age At Onset ◽  
Mrna Levels

scholarly journals Investigation of five polymorphic DNA markers associated with late onset Alzheimer disease

Genetika ◽  
2013 ◽  
Vol 45 (2) ◽  
pp. 503-514 ◽  
Author(s):  
Jalal Gharesouran ◽  
Maryam Rezazadeh ◽  
Mohaddes Mojtaba
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Markers ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
The Elderly ◽  
Healthy Controls ◽  
Genotype Frequencies ◽  
Significant Difference ◽  
And Control

Alzheimer's disease is a complex neurodegenerative disorder characterized by memory and cognitive impairment and is the leading cause of dementia in the elderly. The aim of our study was to examine the polymorphic DNA markers CCR2 (+190 G/A), CCR5?32, TNF-? (-308 G/A), TNF-? (-863 C/A) and CALHM1 (+394 C/T) to determine the relationship between these polymorphisms and the risk of late onset Alzheimer's disease in the population of Eastern Azerbaijan of Iran. A total of 160 patient samples and 163 healthy controls were genotyped by PCR-RFLP and the results confirmed using bidirectional sequencing. Statistical analysis of obtained data revealed non-significant difference between frequency of CCR5?32 in case and control groups. The same result was observed for TNF-? (-863 C/A) genotype and allele frequencies. Contrary to above results, significant differences were detected in frequency of TNF-? (-308 G/A) and CCR2-64I genotypes between the cases and healthy controls. A weak significant difference observed between allele and genotype frequencies of rs2986017 in CALHM1 (+394 C/T; P86L) in patient and control samples. It can be concluded that the T allele of P86L variant in CALHM1 & +190 G/A allele of CCR2 have a protective role against abnormal clinical features of Alzheimer's disease.

scholarly journals Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02A Candidate Tuberculosis Vaccine in Purified Protein Derivative-Negative Adults

2010 ◽  
Vol 17 (11) ◽  
pp. 1763-1771 ◽  
Author(s):  
Isabel Leroux-Roels ◽  
Geert Leroux-Roels ◽  
Opokua Ofori-Anyinam ◽  
Philippe Moris ◽  
Els De Kock ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Response ◽  
Interleukin 2 ◽  
T Cell Response ◽  
Serious Adverse Events ◽  
Purified Protein Derivative ◽  
Tnf Α ◽  
Significant Difference ◽  
Ifn Γ

ABSTRACT Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02A (10 or 40 μg antigen), Mtb72F/saline (10 or 40 μg antigen), or AS02A. Mtb72F/AS02A recipients received an additional dose 1 year after the first dose to evaluate if the elicited immune response could be boosted. Mtb72F/AS02A vaccines were locally reactogenic but clinically well tolerated, with transient adverse events (usually lasting between 1 and 4 days) that resolved without sequelae being observed. No vaccine-related serious adverse events were reported. Vaccination with Mtb72F/AS02A induced a strong Mtb72F-specific humoral response and a robust Mtb72F-specific CD4+ T-cell response, both of which persisted at 9 months after primary immunization and for 1 year after the booster immunization. There was no significant difference between the magnitude of the CD4+ T-cell response induced by the 10-μg and 40-μg Mtb72F/AS02A vaccines. The Mtb72F-specific CD4+ T cells predominantly expressed CD40L; CD40L and interleukin-2 (IL-2); CD40L and tumor necrosis factor alpha (TNF-α); CD40L, IL-2, and TNF-α; and CD40L, IL-2, TNF-α, and gamma interferon (IFN-γ). Serum IFN-γ, but not TNF-α, was detected 1 day after doses 2 and 3 for the Mtb72F/AS02A vaccine but did not persist. Vaccine-induced CD8+ T-cell responses were not detected, and no immune responses were elicited with AS02A alone. In conclusion, Mtb72F/AS02A is clinically well tolerated and is highly immunogenic in TB-naïve adults. The 10- and 40-μg Mtb72F/AS02A vaccines show comparable safety and immunogenicity profiles.

scholarly journals Differences in Multimodal EEG and Clinical Correlations Between Alzheimer’s Disease and Frontotemporal Dementia

2021 ◽  
Author(s):  
Nan Lin ◽  
Jing Gao ◽  
Chenhui Mao ◽  
Heyang Sun ◽  
Qiang Lu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spectral Analysis ◽  
Frontotemporal Dementia ◽  
Clinical Data ◽  
Early Onset ◽  
Late Onset ◽  
Clinical Severity ◽  
Significant Difference ◽  
The Difference

Abstract Background. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two main types of dementia. We aim to investigate the difference between AD and FTD by use of multimodal EEG analyses. Additionally, the difference in correlations between EEG and clinical data was also investigated.Methods. Thirty-one patients diagnosed with AD and 15 patients with FTD were recruited (2008.1-2020.2), along with 24 healthy controls. Clinical data were reviewed. EEG microstate analysis, spectral analyses, and connectivity analysis were performed. Results. Microstate duration was increased in AD for microstate B and increased in FTD for microstate A compared to controls. Correspondingly, microstate C occurrence was decreased in both dementia groups, compared to control group. After divided into early onset and late onset AD, increased mean duration and reduced mean occurrence were observed in early onset AD, compared to late onset AD, with no significant difference in visual EEG score. CSF Aβ42 was correlated to microstate B coverage in AD (r = -0.833, P = 0.010), and microstate D occurrence in FTD (r = 0.786, P = 0.021). ADL and MMSE were also related to visual EEG score and microstate, but for different variables in the two dementia groups. Spectral analysis revealed decreased power in 8-30 Hz and increased power in delta band in both dementia. AD had higher spectral power in the temporal region, compared to FTD. Reduced alpha and beta coherences were demonstrated in AD in bilateral frontal, fronto-temporal, and fronto-occipital connections, and in FTD in the right frontal and fronto-temporal connections. Conclusions. Multimodal EEG analyses show different results between AD and FTD. Reduced coherence is across more brain areas in AD, including intra-anterior and anterior-posterior regions, compared to FTD, which only had frontal-temporal connectivity involved. Spectral analysis revealed a general EEG slowing. Increased microstate duration and decreased occurrence may be attributed to EEG slowing, for different classes in different types of dementia. Microstate may be more sensitive than visual EEG inspection. The correlations with clinical severity and biomarkers indicate that EEG is a potential biomarker for diagnosis and disease assessment.

scholarly journals Association of MS4A6A, CD33, and TREM2 gene polymorphisms with the late-onset Alzheimer’s disease

Bioimpacts ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 219-225 ◽  
Author(s):  
Elham Mehdizadeh ◽  
Mohammad Khalaj-Kondori ◽  
Zeinab Shaghaghi-Tarakdari ◽  
Saeed Sadigh-Eteghad ◽  
Mahnaz Talebi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Polymorphisms ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Salting Out ◽  
Age And Gender ◽  
Blood Samples ◽  
Significant Difference ◽  
And Gender

Introduction: Alzheimer’s disease (AD), which is a progressive neurodegenerative disorder, causes structural and functional brain disruption. MS4A6A, TREM2, and CD33 gene polymorphisms loci have been found to be associated with the pathobiology of late-onset AD (LOAD). In the present study, we tested the hypothesis of association of LOAD with rs983392, rs75932628, and rs3865444 polymorphisms in MS4A6A, TREM2, CD33 genes, respectively.Methods: In the present study, 113 LOAD patients and 100 healthy unrelated age- and gender-matched controls were selected. DNA was extracted from blood samples by the salting-out method and the genotyping was performed by RFLP-PCR. Electrophoresis was carried out on agarose gel. Sequencing was thereafter utilized for the confirmation of the results. Results: Only CD33 rs3865444 polymorphism revealed a significant difference in the genotypic frequencies of GG (P = 0.001) and GT (P = 0.001), and allelic frequencies of G (P = 0.033) and T (P = 0.03) between LOAD patients and controls. Conclusion: The evidence from the present study suggests that T allele of CD33 rs3865444 polymorphism is associated with LOAD in the studied Iranian population.

CD33 mRNA Has Elevated Expression Levels in the Leukocytes of Peripheral Blood in Patients with Late-Onset Alzheimer’s Disease

Gerontology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Fatemeh Heidari ◽  
George Ansstas ◽  
Farzam Ajamian
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mrna Expression ◽  
Peripheral Blood ◽  
In Silico ◽  
Late Onset ◽  
Mrna Levels ◽  
Coding Region ◽  
Expression Levels ◽  
Functional Polymorphisms

<b><i>Background/Aims:</i></b> In despite of conflicting results among different ethnic groups, the rs3865444 of CD33 gene has previously been identified as a risk factor for late-onset Alzheimer’s disease (LOAD).This study was aimed to evaluate the association between rs3865444 SNP with LOAD occurrence, and to investigate whether CD33 mRNA expression will change in the leukocytes of peripheral blood in LOAD patients. <b><i>Methods:</i></b> The rs3865444 polymorphism was genotyped in 233 LOAD and 238 control subjects using the Tetra-ARMS-PCR method. CD33 mRNAs expression in leukocytes were assessed and analyzed using the real-time qPCR method. We used in silico approach to analyze potential effects imparted by rs3865444 polymorphism in LOAD pathogenesis. <b><i>Results:</i></b> Our results show a significant increase in CD33 mRNA expression levels in white blood cells of LOAD patients, however, the association between CD33 rs3865444 polymorphism and LOAD was found to be not significant. We also noticed that LOAD patients with the C/A genotype had higher CD33 mRNA levels in their peripheral blood than those of the control group. <b><i>Conclusions:</i></b> rs3865444, located upstream of the 5′CD33 coding region, might positively influence CD33 mRNAs expression in leukocytes of LOAD versus healthy people. This is likely to happen through interfering rs3865444 (C) with the functional activity of several other transcription factors given that rs3865444 is in linkage disequilibrium with other functional polymorphisms in this coding region according to an in silico study. We propose that CD33 mRNAs elevation in peripheral immune cells – as a potential biomarker in LOAD – is related to peripheral immune system impairment.

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