Neuroepigenetics and Alzheimer’s Disease: An Update

Abstract

Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence-a change in phenotype without a change in genotype-which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer's disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD.

Alcohol Extracts From Ganoderma lucidum Delay the Progress of Alzheimer’s Disease by Regulating DNA Methylation in Rodents

“…Many of these altered pathways are considered primary factors in age-related diseases, including cancer, neurodegenerative diseases, atherosclerosis, and inflammation. AD is associated with dysregulation of DNA methylation, histone modifications, and non-coding RNAs (De Jager et al, 2014; Zusso et al, 2018). Further, recent findings point to a role for 5hmC in the development of diseases, including AD, since global levels of 5mC and 5hmC are positively correlated with one another and with markers of AD, including amyloid beta, tau, and ubiquitin loads, potentially opening new pathways for AD treatment through correction of methylation and hydroxymethylation alterations (Coppieters et al, 2014).…”

DNA methylation in the pathology of Alzheimer's disease: from gene to cognition

“…This process takes place mainly in genomic regions abundant in CpG dinucleotides called CpG islands, which are found in both promoters and gene bodies. 4,9,10 DNA methylation in the promoter results in the outward projection of the bulky additional methyl group, leading to the spatial hindrance that prevents the binding of RNA polymerase. 11 These structural changes perturb the attachment of transcription factors to the transcription start site, suppressing gene transcription.…”

“…3 Indeed, collective studies in the field of neuroepigenetics have suggested an association between dysregulated epigenetic modifications and AD. 4 Among the epigenetic mechanisms, histone modifications are relatively more established in relation to their role in AD. Treatments based on histone deacetylase inhibition have shown promising progress in drug development.…”

A frontline defense against neurodegenerative diseases:the development of early disease detection methods

“…Moreover, miRNAs are involved in cerebral inflammatory responses and amyloidogenic pathways. The altered production and metabolism of a few of miRNAs (miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155) may lead to AD-related aberrant molecular pathways including BACE1 hyperactivity, tau hyperphosphorylation, and neuroinflammation [24]. Blood cells may represent another privileged compartmental sources of peripheral indicators of neurodegeneration.…”