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.

Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer's disease

“…A growing body of evidence indicates that epigenetics may play a crucial role in complex age-related neurodegenerative diseases such as AD (Iatrou et al, 2016; Lardenoije et al, 2015a; Van den Hove et al, 2014). Epigenetic processes dynamically regulate gene expression at both the transcriptional and translational level (Choudhuri, 2011).…”

Epigenetics and DNA methylomic profiling in Alzheimer's disease and other neurodegenerative diseases

“…; Iatrou et al . ). Early onset of AD (< 65 years) is generally associated with Mendelian patterns of inheritance, caused by mutations in the amyloid precursor protein ( APP ), and presenilin 1 and 2 genes.…”

Epigenetic Regulations in Neural Stem Cells and Neurological Diseases

“…Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders in the central nervous system, characterized by progressive cognitive decline and loss of neuronal cells [ 73 ]. The pathogenesis of AD has yet to be defined, but there are evidences to support its genetic abnormalities, such as the mutations in β -amyloid precursor gene and presenilin1/2.…”