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Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease using multiple powerful cohorts, focussed Epigenetics and Stem cell metabolomics (PERADES)

Projectomschrijving

Het voornaamste kenmerk van de ziekte van Alzheimer (AD) is geheugenverlies. Het geheugen wordt gereguleerd door de hersenregio de hippocampus. 

Aanpak en resultaten

Wij hebben van 20 AD patiënten en 10 controle personen de hippocampus verzameld, en daarin de activiteit (expressie) van alle genen bepaald. Hierbij hebben wij duizenden genen geïdentificeerd die afwijkend zijn in het AD brein. Deze zijn verdeeld over verschillende biologische functies. Bijvoorbeeld minder actieve neurotransmitter signalen en energieproductie en verhoogde cel-stress en het afweersysteem. Deze genen, en functies geven informatie over het ziekteproces en helpen de ziekte beter te begrijpen.

Het tweede deelproject richtte zich op het vinden van nieuwe genen betrokken bij de ziekte van Alzheimer. Hiervoor maakten we gebruik van een nieuwe techniek die het mogelijk maakt ons erfelijk materiaal in groot detail in kaart te brengen. Met behulp van whole exome sequencing identificeerden we SORL1 als 4e gen dat de ziekte van Alzheimer kan veroorzaken.

Meer informatie

Producten

Titel: Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer’s Disease in a Family with Several Generations of APOE-4 Homozygosity
Auteur: Louwersheimer, Eva, Cohn-Hokke, Petra E., Pijnenburg, Yolande A.L., Weiss, Marjan M., Sistermans, Erik A., Rozemuller, Annemieke J., Hulsman, Marc, van Swieten, John C., van Duijn, Cock M., Barkhof, Frederik, Koene, Teddy, Scheltens, Philip, Van der Flier, Wiesje M., Holstege, Henne
Magazine: Journal of Alzheimer's disease
Titel: Hippocampal transcriptome profiling combined with protein-protein interaction analysis elucidates Alzheimer’s Disease pathways and genes
Auteur: Jeroen G.J. van Rooij, Lieke H.H. Meeter, Shami Melhem, Diana A.T. Nijholt, Tsz Hang Wong, Netherlands Brain Bank, Annemieke Rozemuller, Andre G. Uitterlinden, Joyce C. van Meurs, John C. van Swieten
Magazine: Neurobiology of Aging
Titel: Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
Auteur: Holstege, Henne, van der Lee, Sven J, Hulsman, Marc, Wong, Tsz Hang, van Rooij, Jeroen GJ, Weiss, Marjan, Louwersheimer, Eva, Wolters, Frank J, Amin, Najaf, Uitterlinden, André G, Hofman, Albert, Ikram, M Arfan, van Swieten, John C, Meijers-Heijboer, Hanne, van der Flier, Wiesje M, Reinders, Marcel JT, van Duijn, Cornelia M, Scheltens, Philip
Magazine: European Journal of Human Genetics
Titel: Alzheimer's disease from phenotype to genotype
Auteur: Eva Louwersheimer
Titel: Transcriptome sequencing in post-mortem AD hippocampus
Auteur: J. van Rooij, J. van Swieten
Titel: RNA-Sequencing in Alzheimer's Disease
Auteur: J. van Rooij, J. van Swieten
Titel: Disentangling the Alzheimer's Disease Hippocampal Transcriptome
Auteur: Jeroen van Rooij, Lieke Meeter, Shami Melhem, Diana Nijholt, Annemieke Rozemuller, André Uitterlinden, Joyce van Meurs, John van Swieten
Titel: Post-mortem RNA-Sequencing in Alzheimer's Disease Patients
Auteur: J. van Rooij, J. van Swieten
Titel: The Hippocampal Transcriptional landscape of end-stage Alzheimer’s Disease
Auteur: J van Rooij, J van Swieten

Verslagen


Samenvatting van de aanvraag

36 million people worldwide suffer with dementia, with an estimated 4.6 million new cases identified every year. Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 50–70% of cases; of these approximately 5% of cases have an early onset of symptoms (<65 years). The aetiology of AD is complex and shows heritability of between 56 and 79% in late-onset AD (LOAD) and 92-100%2 in early-onset AD (EOAD). Mutations in three genes (APP, PSEN1 and PSEN2) result in autosomal dominant forms of AD. However, not all EOAD results from dominant mutations/ The vast majority of EOAD is unexplained. Whole exome sequencing in early and late-onset AD cases WES will be performed in different AD populations, including 500 cases from Alzheimercenters VUmc and Erasmus MC in the Netherlands (JVS). We propose to use “omics” technologies to unravel how the various genetic loci, polygenic risk profiles and environmental risk factors discovered, influence methylation and gene expression in the brain. Epigenetic mechanisms regulate reversible changes in gene-expression in response to environmental stimuli that are in part determined by genetics. The fact that many variants identified in GWAS are located in non-coding regions points to a key role for gene regulation in the pathogenesis of AD that will remain undetected by exome sequencing. Most studies of the transcriptome and epigenome of AD have targeted selected genes or have used array technology which is biased by probe design and does not allow absolute quantification. We aim to generate epigenomic profiles in combination with transcriptomic profiles, using next generation sequencing technology in different regions of the brain. By combining our autopsy material with genetic-epidemiological resources, we aim to begin to uncover the relationships between genes and environment on the one hand and the epigenome and transcriptome on the other. To further understand the molecular events which trigger AD we aim to study the metabolome, which is the endpoint of gene translation, capturing the effect of the genetic and environmental interactions on the proteome. We will separate by means of microlaser dissection the dentate gyrus and CA3 region of 20 brains of patients with early Braak stage, 20 with late Braak stage and 20 normal brains. In addition, we will generate early differentiating neurons from immature pluripotent stem cells obtained from skin biopsies of 20 patients with AD (sporadic, familial and known gene mutation) and 20 controls which will be compared to the blood based IPSC in 2.4.1. We will use the illumina standard RNA-Seq kit for RNA sequencing and the Illumina Infinium HumanMethylation450 BeadChip in the brain cells. The software program TopHat will be used to process and align the reads to the reference genome. The software program Cufflinks will construct a minimum set of transcripts that best described the aligned reads in the dataset. Cuffdiff will then re-estimate the abundance of transcripts listed in the GTF files. The top 30 most over – and under-expressed genes in AD compared to controls can be investigated in more detail. NCBI web-based functional annotation tool DAVID will be used to investigate the functional associations of gene expression changes in AD

Kenmerken

Projectnummer:
733051022
Looptijd: 100%
Looptijd: 100 %
2014
2018
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. J.C. van Swieten