title: Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer's disease: looking in the correct place at the right time?
abstract: Even though the etiology of Alzheimer's disease (AD) remains unknown, it is suggested that an interplay among genetic, epigenetic and environmental factors is involved. An increasing body of evidence pinpoints that dysregulation in the epigenetic machinery plays a role in AD. Recent developments in genomic technologies have allowed for high throughput interrogation of the epigenome, and epigenome-wide association studies have already identified unique epigenetic signatures for AD in the cortex. Considerable evidence suggests that early dysregulation in the brainstem, more specifically in the raphe nuclei and the locus coeruleus, accounts for the most incipient, non-cognitive symptomatology, indicating a potential causal relationship with the pathogenesis of AD. Here we review the advancements in epigenomic technologies and their application to the AD research field, particularly with relevance to the brainstem. In this respect, we propose the assessment of epigenetic signatures in the brainstem as the cornerstone of interrogating causality in AD. Understanding how epigenetic dysregulation in the brainstem contributes to AD susceptibility could be of pivotal importance for understanding the etiology of the disease and for the development of novel diagnostic and therapeutic strategies.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6200 MD, Maastricht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Iatrou
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6200 MD, Maastricht, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Kenis
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6200 MD, Maastricht, The Netherlands.
authors.forename: B P F
authors.initials: BP
authors.lastname: Rutten
authors.affiliation: University of Exeter Medical School, RILD, University of Exeter, Barrack Road, Devon, UK.
authors.forename: K
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6200 MD, Maastricht, The Netherlands. d.vandenhove@maastrichtuniversity.nl.|Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080, Würzburg, Germany. d.vandenhove@maastrichtuniversity.nl.
authors.forename: D L A
authors.initials: DL
authors.lastname: van den Hove
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D065847:Dorsal Raphe Nucleus / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D006801:Humans
keywords: Alzheimer’s disease; DNA hydroxymethylation; DNA methylation; Epigenetics; Locus coeruleus; Raphe nuclei