Increased isoform-specific phosphodiesterase 4D expression is associated with pathology and cognitive impairment in Alzheimer's disease

Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and -D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.This work was financially supported by grants from ISAO/Alz-heimer Nederland WE.03-2016-07, Young European Research Universities Network (YERUN), and the Baeter Laeve foundation. Additional funds have been provided by the Internationale StichtingAlzheimer Onderzoek (ISAO)/Alzheimer Netherlands (Award#11532; Funded by the Dorpmans-Wigmans Foundation) (DvdH),and by the Joint Programme Neurodegenerative Disease Research(JPND) for the EPI-AD consortium (http://www.neurodegenerationresearch.eu/wp-content/uploads/2015/10/Factsheet_EPI-AD.pdf).The project is supported through the following funding organizations under the aegis of JPND; The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw);United Kingdom, Medical Research Council; Germany, German Federal Ministry of Education and Research (BMBF); Luxembourg, National Research Fund (FNR). This project has received funding from the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 643417.We thank Dr. Ir. Jochen De Vry for primer and qPCR experiment designpublished version, accepted version (12 month embargo

An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene

A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.MC_PC_17214/MRC_/Medical Research Council/United Kingdom BHF_/British Heart Foundation/United Kingdom DH_/Department of Health/United Kingdom MR/N027973/1/MRC_/Medical Research Council/United Kingdom WT_/Wellcome Trust/United Kingdom CSO_/Chief Scientist Office/United Kingdom R01 AG036039/AG/NIA NIH HHS/United States 171/ALZS_/Alzheimer's Society/United Kingdompublished version, accepted version (12 month embargo

An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene

This is the final version. Available from the publisher via the DOI in this record.A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage.Alzheimer's Society, United KingdomMedical Research Council (MRC)NIH, United States, R01 grantAlzheimer's Research U

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders

Background People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. Results We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson’s disease (and none with Alzheimer’s disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. Conclusions We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences

Health-related effects and improving extractability of cereal arabinoxylans

Arabinoxylans (AXs) are major dietary fibers. They are composed of backbone chains of -(1–4)- linked xylose residues to which -l-arabinose are linked in the second and/or third carbon positions. Recently, AXs have attracted a great deal of attention because of their biological activities such as their immunomodulatory potential. Extraction of AXs has some difficulties; therefore, various methods have beenusedto increase the extractability ofAXs withvaryingdegrees of success, suchas alkaline, enzymatic, mechanical extraction. However, some of these treatments have been reported to be either expensive, such as enzymatic treatments, or produce hazardous wastes and are non-environmentally friendly, such as alkaline treatments. On the other hand, mechanical assisted extraction, especially extrusion cooking, is an innovative pre-treatment that has been used to increase the solubility of AXs. The aim of the current review article is to point out the health-related effects and to discuss the current research on the extraction methods of AXs

Identifying DNA Methylation Signatures in Alzheimer's Disease Blood

Alzheimer’s disease is a complex, multifaceted disorder, which is estimated to affect over thirty six million people worldwide and is characterised by progressive neurodegeneration and cognitive decline. As the numerous genomic susceptibility loci that have been identified for the most common, sporadic form of Alzheimer’s disease do not fully account for the disease risk, epigenetic and environmental factors have been suggested to be involved in the aetiology and development of Alzheimer’s disease. Epigenetics, of which DNA methylation is perhaps the most studied mechanism, refers to transient, heritable changes in gene expression without the underlying genotype being altered. A growing number of epigenome-wide association studies have demonstrated robust differential DNA methylation in the brain of Alzheimer’s disease patients, though limited studies have been undertaken in blood. The aim of this thesis was to characterise blood DNA methylation profiles in Alzheimer’s disease, as well as individuals with mild cognitive impairment, who often progress to Alzheimer’s disease. Disease-associated profiles were characterised on autosomal chromosomes as well as sex chromosomes, and the effects and interactions of the Alzheimer’s disease risk factors sex and age were studied. The results from this thesis have provided novel insights into DNA methylation changes in blood related to Alzheimer’s disease, mild cognitive impairment, and future progression to Alzheimer’s disease. A region in the HOXB6 gene was found to be differentially methylated in Alzheimer’s disease, which presents an interesting target for future diagnostic biomarker studies. The results concerning the risk factors sex and age, and DNA methylation of the sex chromosomes, emphasise the importance of not only controlling for, but taking into account these factors

Does it make a difference who tells you to conserve energy? : exploring the effect of social agency on psychological reactance

Abstract only