Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Abstract

Here, we leverage a unique collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We find that the level of methylation at 71 of the 415,848 interrogated CpGs is significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validate 11 of the differentially methylated regions in an independent set of 117 subjects. Further, we functionally validate these CpG associations and identify the nearby genes whose RNA expression is altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD since (1) they are seen in presymptomatic subjects and (2) six of the validated genes connect to a known AD susceptibility gene network.

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Two reports (De Jager et al, 2014; Lunnon et al, 2014) established that changes in DNA methylation are associated with AD, and more specifically, a differentially methylated region in ankyrin 1 ( ANK1 ) was found to be associated with the neuropathology. A recent report (Zhao et al, 2017) also links 5hmC with AD.…”

iRhoms in the brain – a new frontier?

“…Stefan F Lichtenthaler 1,2,3,4 , Bruce F O'Hara 5 , and Carl P Blobel 4,6,7 The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) orchestrates cell-cell interactions and has a key role in inflammation, development and in diseases such as Rheumatoid Arthritis and Cancer. ADAM17 is responsible for liberating the pro-inflammatory cytokine TNFa and most EGFR-ligands from their membrane anchor, thereby keeping a close reign on the TNFa-and EGFR signaling pathways.…”

“…One important clue about possible roles of iRhom2 in the brain emerged recently from a study that found an association between the methylation status of the iRhom2 gene and Alzheimer disease. 2 Inflammation is thought to play an important role in the later stages in the pathogenesis of AD, and the Ab peptides that assemble to form the characteristic amyloid plaques in AD can activate microglia, 3 lending additional support to the notion that iRhom2/ADAM17 might be critical mediators of this pathway. De-methylation of the iRhom2 gene may increase the expression of iRhom2, presumably leading to enhanced ADAM17-dependent release of TNFa (and other substrates), thereby exacerbating the inflammatory component of AD.…”

“…De-methylation of the iRhom2 gene may increase the expression of iRhom2, presumably leading to enhanced ADAM17-dependent release of TNFa (and other substrates), thereby exacerbating the inflammatory component of AD. 2,3 Interestingly, concussions and other forms of traumatic brain injury can also lead to temporary or even permanent cognitive impairment. There is mounting evidence that this depends, at least in part, on activation of the TNFa pathway.…”

Paving the road for the study of epigenetics in neurodegenerative diseases

“…However, this is not the case for Alzheimer's disease: as discussed by Klein et al [6] in this cluster of manuscripts, there are two relatively large eWAS for AD with replicable results [2,9,10]. CpG islands close to ANK1, RPL13, CDH23 and RHBDF2 genes are differentially methylated in AD cases compared to controls.…”